All patients with American Joint Committee on Cancer Stage I or II (T1N0, T1N1, T2N0, T2N1) invasive ductal, breast cancer including not otherwise specified, medullary, papillary, colloid (mucinous), or tubular histologies with lesions ≤3 cm were eligible. Patients were required to have unifocal breast cancer (single focus, which can be encompassed by one lumpectomy). Patients with an extensive intraductal component were excluded. Patients with up to three positive axillary nodes were allowed. Patients were required to have negative margins (>2 mm). Patients were ineligible for the study if they had a history of prior malignancy within the past 5 years (except for non-melanomatous skin cancer).
Treatment technique and imaging
Treatment planning and delivery were required to be performed with the patient in the supine position. A treatment planning computed tomography scan was required to define the clinical target volume (CTV) and planning target volume (PTV). The CTV was defined by uniformly expanding the excision cavity volume by 10–15 mm. Six surgical clips were required and used to help define the boundaries of the cavity volume. However, the CTV was limited to 5 mm from the skin surface and lung–chest wall interface. This study required the computed tomography scan to start at or above the mandible and extend several centimeters below the inframammary fold (including the entire lung). These structures required contouring: CTV, PTV, ipsilateral breast, thyroid, contralateral breast, ipsilateral and contralateral lung, and heart. The shoulders, chin, and contralateral breast were included in the scan (computed tomography scan thickness of ≤0.5 cm). The CTV and PTV and normal tissues were outlined on all computed tomography slices.
The PTV was designed to provide a margin around the CTV to compensate for the variability of treatment setup and motion of the breast with breathing. A minimum of 10 mm around the CTV was required (superior, inferior, medial, and lateral dimension). The PTV was saved and used to generate the beam aperture (with an additional margin to take penumbra into account). Because a substantial part of the PTV often extends outside the patient (especially for superficial cavities) the PTV was then copied to a PTV for evaluation (PTV_EVAL), which was edited. This PTV was limited to exclude the part outside the patient and the first 5 mm of tissue under the skin (to remove most of the build up region for the dose–volume histogram analysis) and excluding (if applicable) the PTV expansion within the lung. This PTV_EVAL was the structure used for dose–volume histogram constraints and analysis. This PTV for evaluation could not be used for beam aperture generation.
Treatment could only be given using 3D-CRT fields. Intensity-modulated radiation therapy was not allowed. Field arrangements were at the discretion of the physician and determined by 3D treatment planning to produce the optimal conformal plan in accordance with volume definitions (see the following section). The treatment plan used for each patient was based on an analysis of the volumetric dose including dose–volume histogram analyses of the PTV and critical normal tissues.
Radiotherapy was recommended to begin within 8 weeks of surgery, if no chemotherapy was given. If chemotherapy was given first, RT was recommended to start a minimum of 2 weeks after the last cycle of chemotherapy. A total of 38.5 Gy in 10 fractions were prescribed to the International Commission on Radiation Units and Measurements 50 reference point dose (usually isocenter). Two fractions per day, each of 3.85 Gy, separated by at least 6 h, were given in 5 consecutive working days (Monday–Friday). Dose calculations with tissue inhomogeneity correction were required. Portal films or portal images of each beam and an orthogonal pair (anteroposterior and lateral) were obtained for the first fraction. Subsequent films or images were obtained on fraction numbers 2, 5, and 9 including an orthogonal pair. Additional individual port films could be taken at the investigator’s discretion.
Dose–volume constraints/normal tissue tolerances
Dose–volume constraints were established for the protocol and have been previously published (10
). These included limitations in dose to: (1) uninvolved breast tissue, (2) ipsilateral and contralateral lung, (3) contralateral breast, (4) heart (different values for right and left-sided lesions), and thyroid. In addition, quality assurance evaluations were established with an ideal plan having the 95% isodose surface covers 100% of the PTV and the maximum dose to the PTV should not exceed the prescription dose by >10%.
Acute and late radiation effects were evaluated and scored using the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0 (CTCAE v3.0) (MedDRA v6.0). The values stated represent the patient’s worst toxicity at any time point.
The current analysis focuses on the following protocol-specified secondary efficacy end points: ipsilateral breast recurrence, ipsilateral nodal failure, distant metastases, mastectomy-free survival (MFS), disease-free survival (DFS), and overall survival (OS). An ipsilateral breast failure (IBF) is defined as biopsy-proven invasive or noninvasive recurrence (except lobular carcinoma in situ) in the ipsilateral breast. Failure rates will also be subdivided by within field, peripheral (in the skin of the treated breast), or extra- field locations. An ipsilateral nodal failure (INF) is defined as an ipsilateral axillary, internal mammary, or supraclavicular recurrence only if accompanied by an IBF. IBF, INF, contralateral breast (CBF), and distant failure (DF) rates were estimated using the cumulative incidence method in which death is a competing risk. For MFS, a failure is defined as a simple mastectomy, a modified radical mastectomy, or death from any cause. For DFS, a failure is any tumor recurrence—including local recurrence, nodal recurrence, distant metastases, contralateral breast cancer—or death. MFS, DFS, and OS rates were estimated using the Kaplan-Meier method.