Radiation Therapy in Treating Women With Locally Recurrent Breast Cancer Previously Treated With Repeat Breast-Preserving Surgery

Study Overview
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Brief Summary
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RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Giving radiation therapy after surgery kill any remaining tumor cells and may be an effective treatment for breast cancer. PURPOSE: This phase II trial is studying how well radiation therapy works in treating women with locally recurrent breast cancer previously treated with repeat breast-conserving surgery.

Detailed Description
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OBJECTIVES: Primary To evaluate skin, breast, and chest wall adverse events occurring within 1 year after completion of 3D-conformal partial-breast re-irradiation following repeat breast-preserving surgery in patients with locally recurrent breast carcinoma. Secondary To evaluate the adverse events occurring after 1 year from the completion of re-irradiation and at any time. To evaluate in-breast control rate in patients treated with this regimen. To evaluate freedom-from-mastectomy rate in these patients. To evaluate the rate of circulating tumor cells (CTCs) in this patient population and to document eradication of CTCs by locoregional therapy. To determine whether translational objective will correlate with eradication or presence of CTCs with in-breast recurrence and distant metastasis-free survival. To evaluate cosmesis as judged by the patient and independent evaluation. To evaluate distant metastasis-free survival, mastectomy-free survival, and overall survival of patients treated with this regimen. OUTLINE: This is a multicenter study. Patients undergo 3-dimensional conformal accelerated partial-breast irradiation twice daily, 5 days a week, for 3 weeks. Some patients undergo blood sample collection at baseline and within 3 weeks after completion of radiotherapy for circulating tumor cells analysis. Some patients complete questionnaires on cosmesis at baseline and at 1 and 3 years following radiotherapy. After completion of study therapy, patients are followed up periodically for 4-5 years and then every year thereafter.

Official Title
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A Phase II Study of Repeat Breast Preserving Surgery and 3D-Conformal Partial Breast Re-Irradiation (PBrI) for Local Recurrence of Breast Carcinoma

Conditions
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Breast Cancer

Intervention / Treatment
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* Radiation: 3D-Conformal External Beam


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed locally recurrent breast carcinoma consistent with the following cell types: Invasive ductal breast carcinoma Medullary ductal breast carcinoma Tubular ductal breast carcinoma Mucinous ductal breast carcinoma Lobular breast carcinoma Ductal carcinoma in situ (DCIS) No Paget disease of the nipple Target lumpectomy cavity must be clearly defined and the target lumpectomy cavity/ whole-breast reference volume must be < 30% based on a post-operative, pre-treatment CT scan Tumor size ≤ 3 cm in greatest dimension on pathologic specimen Negative histologic margins of resection and no tumor on ink following breast-preserving surgery of local recurrence (Re-excision is permitted to achieve negative margins) Axilla negative or ≤ 3 positive lymph nodes without extracapsular extension If the in-breast recurrence is DCIS and/or microinvasive disease, a sentinel lymph node (SLN) evaluation is not required, but if performed: Patients with a negative sentinal lymph node (SLN) biopsy are eligible for enrollment Patients with a positive SLN biopsy require an axillary lymph node (ALN) dissection (ALND is not required if the SLN is not identified) Patient is eligible if 0-3 positive ALNs without extracapsular extension is documented If the in-breast recurrence is invasive disease and: No prior ALN dissection or SLN dissection only: Patient is required to undergo axillary evaluation with either a SLN or ALN dissection If the SLN is not identified or if the SLN is positive for metastatic disease then an ALN dissection is required Patient is eligible for enrollment if encounter 0-3 positive lymph nodes without extracapsular extension • Prior ALN dissection: negative clinical exam: patient is eligible for enrollment It is recommended, but not required, that the patient undergo ultrasound evaluation of the axilla and the lymph node draining regions of the breast; any suspicious areas are to be biopsied and if positive followed with an ALN dissection Patient is eligible for enrollment if biopsies are negative or 0-3 axillary lymph nodes without extracapsular extension are encountered Prior ALN dissection: positive clinical exam: biopsy required If biopsy is negative, patient is eligible for enrollment If biopsy is positive an ALN dissection is required Patient is eligible for enrollment if biopsies are negative or 0-3 axillary lymph nodes without extracapsular extension encountered Ipsilateral breast mammogram and MRI within 120 days prior to study entry Contralateral breast mammogram within 12 months of study entry For invasive in-breast recurrence, no more than 120 days since whole-body (positron emission tomography) PET-CT scan OR CT scan of the chest, abdomen, and pelvis, and bone scan No multicentric ipsilateral breast recurrence or regional recurrence (other than axilla) Patients must have a breast technically amenable to partial-breast irradiation No metastatic disease documented by physical exam or radiographic evaluation (for patients with invasive disease) No skin involvement No prior contralateral mastectomy Estrogen and progesterone status must be known PATIENT CHARACTERISTICS: Zubrod performance status 0-1 Menopausal status not specified Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No other invasive malignancy within the past 3 years except ipsilateral breast cancer and/or nonmelanoma skin cancer No collagenous diseases, specifically systemic lupus erythematosus, scleroderma, or dermatomyositis No psychiatric or addictive disorders that would preclude obtaining informed consent PRIOR CONCURRENT THERAPY: See Disease Characteristics More than 2 weeks since prior chemotherapy and recovered No concurrent intensity-modulated radiotherapy No concurrent chemotherapeutic agents, including trastuzumab

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Partial Breast Re-Irradiation<br>Partial Breast Re-Irradiation (PBrI) 3D-Conformal External Beam 1.5 Gy x 15 (BID) to 45 Gy Total | Radiation: 3D-Conformal External Beam<br>* Radiation was to be delivered in 2 fractions per day, each of 1.5 Gy, separated by at least six hours, given in 15 consecutive working days to a total of 30 fractions and 45 Gy. Radiation was to be prescribed to the treatment unit isocenter, positioned at the approximate center of the planning target volume.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Grade 3+ Treatment-related Skin, Fibrosis, and Breast Pain Adverse Events | Adverse events (AEs) were graded with Common Terminology Criteria for Adverse Events (CTCAE) version 4. Grade refers to the severity of the AE. The Common Terminology Criteria for Adverse Events (CTCAE) v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. Based on a rate of 4% for the AEs of interest, a rate of ≥ 13% for these AEs with re-irradiation would be unacceptable. A sample size of 55 evaluable pts (eligible & started protocol treatment) would provide: 86% power to conclude an unacceptable rate of the specified AEs, if the true AE rate was at least 13%; 93% probability to not conclude an unacceptable rate of the specified AEs, if the true AE rate is 4%. If ≥ 5 pts have treatment-related AEs, then the treatment-related AE rate was considered unacceptable. | From the end of radiation to 1 year. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| In-breast Recurrence | The definition of treatment failure is histologic evidence of recurrent carcinoma, either invasive or non-invasive (except LCIS) in the ipsilateral breast. Clinical evidence of carcinoma by physical examination and/or mammograms and/or MRI will not be construed as evidence of treatment failure without biopsy proof but will be considered as suspicious for recurrence. Ipsilateral breast recurrences will be considered local (infield) if they occur within the prescription isodose volume; they will be considered peripheral if they occur between the prescription isodose volume and a volume 2 cm outside of the prescription isodose volume. Ipsilateral recurrences will be considered non-contiguous or extra field if they are beyond the peripheral volume described above. | From registration to date of recurrence or last follow-up. Analysis occurs after all patients have been potentially followed for 3 years. | 
| Freedom From Mastectomy | Failure is mastectomy of the treated breast. Mastectomy rate at 3 years is reported, using the cumulative incidence with death as competing risk. Mastectomy-free survival is reported in outcome measure 10. | From registration to date of mastectomy or last follow-up. Analysis occurs after all patients have been potentially followed for 3 years. | 
| Number of Patients With Detectable/Undetectable/Unevaluable Circulating Tumor Cells (CTCs) | CTCs in peripheral blood were assessed using the CellSearch (trademark) system. A stringent algorithm was used to classify cell images as a CTC. A CTC must express EpCAM [epithelial cell adhesion molecule] and not leukocyte lineage-specific antigens, exhibit cytoplasmic expression of cytokeratin, and contain a nucleus that binds DAPI [4',6-doamidino-2-phenylindole]. A cell image is not a CTC if any of the previous criterion are missing. A subject is categorized as Detectable if the patient had a CTC and Undetectable if the subject had no CTCs. If neither category could be determined, then the subject was categorized as Unevaluable. | Prior to the start of radiation and 3 weeks after last radiation treatment. | 
| Treatment-related Adverse Events (AEs) Any Time | AEs were graded with Common Terminology Criteria for Adverse Events (CTCAE) version 4. Grade refers to the severity of the AE. The Common Terminology Criteria for Adverse Events (CTCAE) v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. The overall highest grade for each patient was computed from all reported adverse events definitely, probably, or possibly related to protocol treatment. | From the end of radiation to end of follow-up. Will be evaluated at the time of the primary analysis. | 
| Distant Metastasis-free Survival | Failures are appearance of ipsilateral axillary, infraclavicular, internal mammary, or supraclavicular recurrences; distant metastases confirmed radiographically and/or pathologically; or death due to any cause. Note that a distant metastases was only considered a treatment failure if accompanied by an in-breast recurrence. | From registration to date of distant metastasis, death or last follow-up. Analysis occurs after all patient have been potentially followed for 3 years. | 
| Mastectomy-free Survival | Failure is mastectomy of the treated breast or death due to any cause. Mastectomy-free survival rate at three years was estimated using the Kaplan-Meier method. | From registration to date of mastectomy, death or last follow-up. Analysis occurs after all patients have been potentially followed for 3 years. | 
| Overall Survival | Failure is death due to any cause. Three-year overall survival rate was estimated using the Kaplan-Meier method. | From registration to date of death or last follow-up. Analysis occurs after all patients have been potentially followed for 3 years. | 
| Treatment-related Adverse Events Occurring After One Year From Completion of Re-irradiation | AEs were graded with CTCAE version 4. The overall highest grade for each patient is computed from reported adverse events definitely, probably, or possibly related to protocol treatment occurring after one year from completion of re-irradiation. | After 1 year from the end of radiation. | 
| Change in Patient-Reported Cosmetic Outcomes From Baseline to 12-Months as Measured by the Breast Cancer Treatment Outcome Scale (BCTOS) | The Breast Cancer Treatment Outcome Scale (BCTOS) is a 22-item tool to assess cosmetic results using patient self-reports. This brief self-report instrument has high reliability and validity, and it has been used in a variety of previous studies on recovery from breast cancer treatment. It is comprised of three subscales (functional status, cosmetic status, and breast specific pain). Response options for each BCTOS item form a four-point Likert scale evaluating the differences between the treated and the untreated breast (1=no, 2=slight, 3=moderate, 4=large difference). The score for each subscale is the mean of the ratings over all items belonging to that specific subscale. Change was calculated as the value at 12 months minus the value at baseline. A positive change reflects a decline at 12 months and a negative change reflects an improvement at 12 months. | Baseline and 12 months from the start of radiation treatment. | 
| Change in Patient-Reported Cosmetic Outcomes From Baseline to 36-Months as Measured by the Breast Cancer Treatment Outcome Scale (BCTOS) | The Breast Cancer Treatment Outcome Scale (BCTOS) is a 22-item tool to assess cosmetic results using patient self-reports. This brief self-report instrument has high reliability and validity, and it has been used in a variety of previous studies on recovery from breast cancer treatment. It is comprised of three subscales (functional status, cosmetic status, and breast specific pain). Response options for each BCTOS item form a four-point Likert scale evaluating the differences between the treated and the untreated breast (1=no, 2=slight, 3=moderate, 4=large difference). The score for each subscale is the mean of the ratings over all items belonging to that specific subscale. Change was calculated as the value at 36 months minus the value at baseline. A positive change reflects a decline at 36 months and a negative change reflects an improvement at 36 months. | Baseline and 36 months from the start of radiation treatment. | 
| Number of Patients With Good/Excellent Cosmesis Using the NRG Oncology/Radiation Therapy Oncology Group (RTOG) Cosmetic Rating Scale | Physicians rated cosmesis using a 4 point NRG Oncology/RTOG established criteria scale: Excellent - when compared to the untreated breast or the original appearance of the breast, there is minimal/no difference in the size or shape of the treated breast. Good - there is a slight difference in the size or shape of the treated breast as compared to the opposite breast or the original appearance of the treated breast. Fair - obvious differences in the size and shape of the treated breast. This change involves quarter or less of the breast. Poor - marked change in the appearance of the treated breast involving more than a quarter of the breast tissue. | Baseline,12, and 36 Months from the start of radiation treatment. | 
| 12-Month BCTOS Mean Subscale Scores by 12-Month NRG Oncology/RTOG Cosmetic Rating Scale | Patient-Reported BCTOS is comprised of 3 subscales (functional status, cosmetic status, breast specific pain). Responses for each item form a 4-point Likert scale evaluating the differences between the treated and untreated breast (1=no, 2=slight, 3=moderate, 4=large difference). Higher scores reflect poorer outcomes. Physicians rated cosmesis using a 4 point NRG Oncology/RTOG established criteria scale: Excellent - when compared to the untreated breast or the original appearance of the breast, there is minimal/no difference in the size or shape of the treated breast. Good - there is a slight difference in the size or shape of the treated breast as compared to the opposite breast or the original appearance of the treated breast. Fair - obvious differences in the size and shape of the treated breast. This change involves quarter or less of the breast. Poor - marked change in the appearance of the treated breast involving more than a quarter of the breast tissue. | 12 Months from the start of radiation treatment. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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invasive ductal breast carcinoma, medullary ductal breast carcinoma with lymphocytic infiltrate, invasive lobular breast carcinoma, tubular ductal breast carcinoma, mucinous ductal breast carcinoma, ductal breast carcinoma in situ, lobular breast carcinoma in situ, recurrent breast cancer