Breast Cancer
Conditions
Keywords
Breast Cancer, Radiation, Hypofractionation, Randomization
Brief summary
This study is a randomized trial of hypofractionation (short-course) radiation therapy versus conventional radiation therapy in women who have undergone mastectomy and immediate breast reconstruction. The investigators will assess cosmetic and reconstruction outcomes, lymphedema, cancer status, side effects, and oncologic outcomes.
Detailed description
Over 180,000 diagnoses of invasive breast cancer are made in the US each year. Over one-third of women with early stage and over half with late-stage breast cancer are treated with mastectomy (removal of the entire breast) due to tumor size, multiple cancers within the breast, genetic cancer predisposition, and/or patient preference. Following treatment with mastectomy, women who receive breast reconstructive surgery may experience better quality of life as they do not have to leave surgery with a bare chest wall. However, large randomized trials of post-mastectomy radiation therapy reveal a survival benefit with the addition of radiation after mastectomy in women who have cancer present in the axillary lymph nodes (6). The delivery of radiation therapy in the presence of a breast reconstruction is challenging and often leads to undesirable consequences including reconstruction loss, need for major surgical revision, or poor cosmetic outcomes. Therefore, oncologists and patients are forced to decide between the potential for improved oncologic outcomes with radiation therapy versus increased likelihood of complications and suboptimal cosmetic results. Because of this, some patients may be foregoing reconstruction if radiation therapy after mastectomy is needed; or foregoing radiation therapy if they have had breast reconstructive surgery (28). Hypofractionation enhances patient convenience and decreases treatment burden. This regimen has been shown in randomized trials largely in the breast-conservation setting to reduce acute radiation therapy side-effects, decrease fatigue at six months and improve cosmetic results (21, 22). Despite these results, adoption of hypofractionation has been slow among women with breast cancer treated with breast-conserving surgery (24, 25) likely due to familiarity and experience of conventional long-course radiation therapy. While hypofractionation is used commonly in the UK for patients with mastectomy, there are no randomized studies particularly studying outcomes following shorter course radiation therapy in women who undergo mastectomy with breast reconstruction. Therefore, there is an even greater barrier to the use of hypofractionation in this setting in the US. With improved cosmetic results found with hypofractionation, this shorter regimen may have the potential to improve reconstruction success rates which are unfortunately modest overall, for patients who require post-mastectomy radiation. Especially in contrast to financial disincentives to reduce number of radiation treatments, Level I randomized evidence is needed in this population to change practice patterns regarding radiation regimen. Our study of radiation fractionation regimens has the potential to increase use of hypofractionation among women treated with mastectomy, thereby decreasing treatment burden. Our team of patient stakeholders ensures that our outcomes measures encompass all domains of survivorship after breast cancer (physical and mental health as well as satisfaction with the decision-making process). Despite the large numbers of breast cancer survivors who undergo mastectomy, reconstruction and radiation therapy, little is known about which domains of quality of life are affected and their importance to these patients. This study uses previously validated tools for measuring patient outcomes, and have added questions for areas which are important to patients that may not have been captured adequately by previous tools. In concert with the increasing awareness of the importance of survivorship care to cancer care, identifying a comprehensive set of outcomes measurement tools following treatment with radiation therapy, mastectomy, and reconstruction is an important asset for future treatment evaluation in these women.
Interventions
RADIATIONRadiation Therapy
For the conventional fractionation arm: Each fraction will consist of 200 cGy per day. Total dose = 5000 cGy to the chest wall and 4600-5000 cGy to the lymph nodes. For the hypofractionation arm: Each fraction consists of 266 cGy per day. Total dose = 4256 cGy to the chest wall and 3990 cGy to the lymph nodes.
Sponsors
Patient-Centered Outcomes Research Institute
Dana-Farber Cancer Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Diagnosed with clinical or pathologic stage I-III invasive breast cancer with TX-T3 tumor 2. Has been treated with mastectomy 3. Has undergone immediate reconstructive surgery with placement of a tissue expander or permanent implant at time of mastectomy 4. Is a candidate for unilateral post-mastectomy radiation therapy as per National Comprehensive Cancer Network (NCCN) guidelines (post-mastectomy radiation therapy is indicated for most patients with positive lymph nodes at time of surgery and infrequently for selected node-negative patients) 5. Use of bolus is permitted, but not required 6. Age ≥18
Exclusion criteria
1. T4 cancer 2. Recurrent breast cancer or history of prior breast radiation therapy 3. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, and/or mental health illness that the consenting investigator feels would affect patient's ability to participate in this study 4. Pregnant or nursing 5. History of a different malignancy except for the following circumstances: * Disease-free for at least five years and deemed by the investigator to be at low risk for recurrence of that malignancy (\<5 %). * Cervical cancer in situ and basal cell or squamous cell carcinoma of the skin 6. Breast cancer requiring bilateral breast/chest wall radiation therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Patient Reported Outcomes Using the FACT-B | 6 months | The primary outcome is the change at 6 months from baseline in patient-reported outcomes on the Physical Well Being (PWB) sub-domain of the Functional Assessment of Cancer Therapy-Breast (FACT-B) instrument. The FACT-B is a 37-item instrument designed to measure five domains of health-related quality of life in breast cancer patients. The higher the score, the better the quality of life. Score ranges: * The score range for the FACT-B total score is 0-148. * The score range for the PWB, social/family well-being (SWB), and functional well-being (FWB) subscales is 0-28. * The score range for the emotional well-being (EWB) subscale is 0-24. * The score range for the breast cancer subscale (BCS) is 0-40. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Oncologic and Clinical Outcomes Assessed Using Medical Record Abstractions. | 10 years | Clinical and oncologic outcomes (rare radiation side effects, recurrence, infections, additional surgeries) will be assessed over a period of 10 years through annual medical record abstractions. |
| Cosmetic Outcomes Assessed Using Photographic Evaluations. | 18 months | Cosmetic outcomes (quality of reconstructive surgery throughout and after radiation therapy) will be assessed from baseline to 18 months by trained physicians using a standardized rating scale. |
Countries
United States
Participant flow
Pre-assignment details
The following are reasons for withdrawal from the study before starting protocol treatment: * patients withdrew due to the treatment arm assignment * patients withdrew due to a change in treatment site * clinician withdrew patients due to tissue expander removal and other treatment needs
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: Hypofractionation 16 fractions of radiation therapy (daily, Monday through Friday) to the chest wall with or without internal mammary nodes, and 15 fractions to the supraclavicular (with or without axillary) lymph nodes.
Radiation Therapy: For the conventional fractionation arm: Each fraction will consist of 200 cGy per day. Total dose = 5000 cGy to the chest wall and 4600-5000 cGy to the lymph nodes.
For the hypofractionation arm: Each fraction consists of 266 cGy per day. Total dose = 4256 cGy to the chest wall and 3990 cGy to the lymph nodes. | 199 |
| Arm 2: Conventional Radiation Therapy 25 fractions of radiation therapy (daily, Monday through Friday) to the chest wall with or without internal mammary nodes, and 23-25 fractions to the supraclavicular (with or without axillary) lymph nodes.
Radiation Therapy: For the conventional fractionation arm: Each fraction will consist of 200 cGy per day. Total dose = 5000 cGy to the chest wall and 4600-5000 cGy to the lymph nodes.
For the hypofractionation arm: Each fraction consists of 266 cGy per day. Total dose = 4256 cGy to the chest wall and 3990 cGy to the lymph nodes. | 201 |
| Total | 400 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 6-month Follow-up | Withdrawal by subject, loss to follow-up | 26 | 33 |
| Baseline | Some participants skipped the survey question related to the primary outcome being analyzed. | 7 | 2 |
Baseline characteristics
| Characteristic | Arm 1: Hypofractionation | Arm 2: Conventional Radiation Therapy | Total |
|---|---|---|---|
| Age, Customized Age 40-50 years | 84 Participants | 90 Participants | 174 Participants |
| Age, Customized Age <40 years | 42 Participants | 41 Participants | 83 Participants |
| Age, Customized Age 51-60 years | 49 Participants | 42 Participants | 91 Participants |
| Age, Customized Age 60+ years | 19 Participants | 19 Participants | 38 Participants |
| Age, Customized Age Missing | 5 Participants | 9 Participants | 14 Participants |
| Axillary Node Dissection No | 99 Participants | 112 Participants | 211 Participants |
| Axillary Node Dissection Yes | 100 Participants | 89 Participants | 189 Participants |
| Axillary Nodes Removed | 8.5 Nodes | 9.0 Nodes | 9 Nodes |
| BMI 20.0-24.9 (kg/m^2) | 79 Participants | 75 Participants | 154 Participants |
| BMI <20 (kg/m^2) | 18 Participants | 11 Participants | 29 Participants |
| BMI 25.0-29.9 (kg/m^2) | 55 Participants | 60 Participants | 115 Participants |
| BMI 30.0-34.9 (kg/m^2) | 30 Participants | 34 Participants | 64 Participants |
| BMI Greater than or equal to 35.0 (kg/m^2) | 16 Participants | 20 Participants | 36 Participants |
| BMI Missing | 1 Participants | 1 Participants | 2 Participants |
| Cancer Laterality Laterality: Left | 86 Participants | 107 Participants | 193 Participants |
| Cancer Laterality Laterality: Right | 113 Participants | 93 Participants | 206 Participants |
| Cancer Laterality Missing | 0 Participants | 1 Participants | 1 Participants |
| Device irradiated Expander | 160 Participants | 156 Participants | 316 Participants |
| Device irradiated Implant | 39 Participants | 45 Participants | 84 Participants |
| Education College graduate | 63 Participants | 57 Participants | 120 Participants |
| Education Missing | 4 Participants | 1 Participants | 5 Participants |
| Education No College | 20 Participants | 29 Participants | 49 Participants |
| Education Some college | 32 Participants | 42 Participants | 74 Participants |
| Education Some graduate/graduate degree | 80 Participants | 72 Participants | 152 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 19 Participants | 27 Participants | 46 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 180 Participants | 174 Participants | 354 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| HER2 Status Equivocal | 11 Participants | 11 Participants | 22 Participants |
| HER2 Status Negative | 146 Participants | 149 Participants | 295 Participants |
| HER2 Status Positive | 42 Participants | 39 Participants | 81 Participants |
| HER2 Status Unknown | 0 Participants | 2 Participants | 2 Participants |
| Histology Both | 25 Participants | 14 Participants | 39 Participants |
| Histology Invasive Ductal | 139 Participants | 147 Participants | 286 Participants |
| Histology Invasive Lobular | 29 Participants | 32 Participants | 61 Participants |
| Histology Other | 6 Participants | 8 Participants | 14 Participants |
| Hormone Receptor Status Negative | 37 Participants | 27 Participants | 64 Participants |
| Hormone Receptor Status Positive | 162 Participants | 174 Participants | 336 Participants |
| Location of Device Not applicable/Unknown | 0 Participants | 4 Participants | 4 Participants |
| Location of Device Pre-pectoral | 115 Participants | 118 Participants | 233 Participants |
| Location of Device Sub-pectoral | 84 Participants | 79 Participants | 163 Participants |
| Lymphatic Vessel Invasion (LVI) Missing | 2 Participants | 2 Participants | 4 Participants |
| Lymphatic Vessel Invasion (LVI) Negative | 118 Participants | 126 Participants | 244 Participants |
| Lymphatic Vessel Invasion (LVI) Other | 79 Participants | 73 Participants | 152 Participants |
| Neoadjuvant Chemotherapy No | 62 Participants | 67 Participants | 129 Participants |
| Neoadjuvant Chemotherapy Unknown | 0 Participants | 0 Participants | 0 Participants |
| Neoadjuvant Chemotherapy Yes | 137 Participants | 134 Participants | 271 Participants |
| Neoadjuvant endocrine therapy No | 152 Participants | 162 Participants | 314 Participants |
| Neoadjuvant endocrine therapy Unknown | 1 Participants | 0 Participants | 1 Participants |
| Neoadjuvant endocrine therapy Yes | 46 Participants | 39 Participants | 85 Participants |
| Prior Infection No | 188 Participants | 187 Participants | 375 Participants |
| Prior Infection Yes | 11 Participants | 14 Participants | 25 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 21 Participants | 12 Participants | 33 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 8 Participants | 14 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 15 Participants | 20 Participants | 35 Participants |
| Race (NIH/OMB) White | 157 Participants | 161 Participants | 318 Participants |
| Radiation Therapy Chest Wall alone | 19 Participants | 23 Participants | 42 Participants |
| Radiation Therapy Chest Wall and Nodes | 170 Participants | 160 Participants | 330 Participants |
| Radiation Therapy Missing due to study withdrawal | 5 Participants | 9 Participants | 14 Participants |
| Region of Enrollment United States | 199 participants | 201 participants | 400 participants |
| Sex: Female, Male Female | 199 Participants | 201 Participants | 400 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Smoking Status Current/Former Smoker | 52 Participants | 61 Participants | 113 Participants |
| Smoking Status Never Smoked | 147 Participants | 140 Participants | 287 Participants |
| Technique 3D-Conformal | 109 Participants | 112 Participants | 221 Participants |
| Technique IMRT | 82 Participants | 78 Participants | 160 Participants |
| Technique Missing | 3 Participants | 2 Participants | 5 Participants |
| Time from surgery to RT (months) (Median, Q1, Q3) | 2.7 Months | 2.4 Months | 2.5 Months |
| Total number of positive nodes 0 nodes | 56 Participants | 52 Participants | 108 Participants |
| Total number of positive nodes 1 node | 65 Participants | 76 Participants | 141 Participants |
| Total number of positive nodes 2 nodes | 33 Participants | 32 Participants | 65 Participants |
| Total number of positive nodes 3 or more nodes | 38 Participants | 34 Participants | 72 Participants |
| Total number of positive nodes Missing | 7 Participants | 7 Participants | 14 Participants |
| Tumor Grade Moderately Differentiated (Grade 2) | 95 Participants | 96 Participants | 191 Participants |
| Tumor Grade Not applicable | 2 Participants | 1 Participants | 3 Participants |
| Tumor Grade Poorly Differentiated (Grade 3) | 82 Participants | 78 Participants | 160 Participants |
| Tumor Grade Well Differentiated (Grade 1) | 20 Participants | 26 Participants | 46 Participants |
| Tumor Size Greater than 2 cm - Less than or equal to 5 cm | 60 Participants | 49 Participants | 109 Participants |
| Tumor Size Greater than 5cm | 21 Participants | 23 Participants | 44 Participants |
| Tumor Size Less than or equal to 2 cm | 99 Participants | 114 Participants | 213 Participants |
| Tumor Size Missing | 19 Participants | 15 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 199 | 2 / 201 |
| other Total, other adverse events | 4 / 199 | 2 / 201 |
| serious Total, serious adverse events | 37 / 199 | 29 / 201 |
Outcome results
Primary
Patient Reported Outcomes Using the FACT-B
The primary outcome is the change at 6 months from baseline in patient-reported outcomes on the Physical Well Being (PWB) sub-domain of the Functional Assessment of Cancer Therapy-Breast (FACT-B) instrument. The FACT-B is a 37-item instrument designed to measure five domains of health-related quality of life in breast cancer patients. The higher the score, the better the quality of life. Score ranges: * The score range for the FACT-B total score is 0-148. * The score range for the PWB, social/family well-being (SWB), and functional well-being (FWB) subscales is 0-28. * The score range for the emotional well-being (EWB) subscale is 0-24. * The score range for the breast cancer subscale (BCS) is 0-40.
Time frame: 6 months
Population: Some participants skipped the survey questions related to the primary outcome being analyzed. This is why there is a discrepancy between the number analyzed for each domain and the total number of participants in each arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1: Hypofractionation | Patient Reported Outcomes Using the FACT-B | 6-month FACT-B | 105.0 score on a scale | Standard Deviation 15 |
| Arm 1: Hypofractionation | Patient Reported Outcomes Using the FACT-B | Baseline EWB | 16.2 score on a scale | Standard Deviation 2.8 |
| Arm 1: Hypofractionation | Patient Reported Outcomes Using the FACT-B | 6-month PWB | 23.0 score on a scale | Standard Deviation 4.1 |
| Arm 1: Hypofractionation | Patient Reported Outcomes Using the FACT-B | Baseline PWB | 22.4 score on a scale | Standard Deviation 5 |
| Arm 1: Hypofractionation | Patient Reported Outcomes Using the FACT-B | 6-month SWB | 22.4 score on a scale | Standard Deviation 4.9 |
| Arm 1: Hypofractionation | Patient Reported Outcomes Using the FACT-B | Baseline FWB | 16.7 score on a scale | Standard Deviation 4.4 |
| Arm 1: Hypofractionation | Patient Reported Outcomes Using the FACT-B | 6-month EWB | 16.5 score on a scale | Standard Deviation 3.2 |
| Arm 1: Hypofractionation | Patient Reported Outcomes Using the FACT-B | Baseline SWB | 23.8 score on a scale | Standard Deviation 4.1 |
| Arm 1: Hypofractionation | Patient Reported Outcomes Using the FACT-B | 6-month FWB | 17.7 score on a scale | Standard Deviation 4.3 |
| Arm 1: Hypofractionation | Patient Reported Outcomes Using the FACT-B | Baseline BCS | 25.3 score on a scale | Standard Deviation 4.6 |
| Arm 1: Hypofractionation | Patient Reported Outcomes Using the FACT-B | 6-month BCS | 25.4 score on a scale | Standard Deviation 4.7 |
| Arm 1: Hypofractionation | Patient Reported Outcomes Using the FACT-B | Baseline FACT-B | 104.3 score on a scale | Standard Deviation 14.5 |
| Arm 2: Conventional Radiation Therapy | Patient Reported Outcomes Using the FACT-B | 6-month BCS | 25.4 score on a scale | Standard Deviation 5.4 |
| Arm 2: Conventional Radiation Therapy | Patient Reported Outcomes Using the FACT-B | Baseline FACT-B | 102.4 score on a scale | Standard Deviation 17 |
| Arm 2: Conventional Radiation Therapy | Patient Reported Outcomes Using the FACT-B | Baseline SWB | 23.0 score on a scale | Standard Deviation 4.6 |
| Arm 2: Conventional Radiation Therapy | Patient Reported Outcomes Using the FACT-B | Baseline EWB | 15.8 score on a scale | Standard Deviation 3.5 |
| Arm 2: Conventional Radiation Therapy | Patient Reported Outcomes Using the FACT-B | Baseline FWB | 16.3 score on a scale | Standard Deviation 4.8 |
| Arm 2: Conventional Radiation Therapy | Patient Reported Outcomes Using the FACT-B | Baseline BCS | 24.9 score on a scale | Standard Deviation 5.2 |
| Arm 2: Conventional Radiation Therapy | Patient Reported Outcomes Using the FACT-B | 6-month FACT-B | 103.5 score on a scale | Standard Deviation 17.7 |
| Arm 2: Conventional Radiation Therapy | Patient Reported Outcomes Using the FACT-B | 6-month PWB | 22.4 score on a scale | Standard Deviation 4.7 |
| Arm 2: Conventional Radiation Therapy | Patient Reported Outcomes Using the FACT-B | 6-month SWB | 22.2 score on a scale | Standard Deviation 5 |
| Arm 2: Conventional Radiation Therapy | Patient Reported Outcomes Using the FACT-B | 6-month EWB | 16.1 score on a scale | Standard Deviation 3.8 |
| Arm 2: Conventional Radiation Therapy | Patient Reported Outcomes Using the FACT-B | 6-month FWB | 17.3 score on a scale | Standard Deviation 4.5 |
| Arm 2: Conventional Radiation Therapy | Patient Reported Outcomes Using the FACT-B | Baseline PWB | 22.5 score on a scale | Standard Deviation 4.7 |
Secondary
Cosmetic Outcomes Assessed Using Photographic Evaluations.
Cosmetic outcomes (quality of reconstructive surgery throughout and after radiation therapy) will be assessed from baseline to 18 months by trained physicians using a standardized rating scale.
Time frame: 18 months
Secondary
Oncologic and Clinical Outcomes Assessed Using Medical Record Abstractions.
Clinical and oncologic outcomes (rare radiation side effects, recurrence, infections, additional surgeries) will be assessed over a period of 10 years through annual medical record abstractions.
Time frame: 10 years