This Phase III randomized trial will evaluate the effectiveness of partial breast irradiation (PBI) compared to whole breast irradiation (WBI) in providing equivalent local tumor control in the breast following lumpectomy for early stage breast cancer. The study will compare the overall survival, recurrence-free survival, and distant disease-free survival between women receiving PBI and WBI. It will also look at quality of life (QOL) issues related to cosmesis, fatigue, treatmentrelated symptoms, and perceived convenience of care. To qualify for the trial, patients must have stage 0 (DCIS) or stage I or II invasive adenocarcinoma of the breast with no evidence of metastatic disease. If stage II, tumor size must be 3 cm or less. Women must have undergone a lumpectomy with the margins of the resected specimen histologically free of cancer including DCIS. For patients with positive axillary nodes, eligibility is restricted to those with 0 to 3 positive axillary nodes.

Following stratification, patients will be randomized to receive WBI or PBI. WBI for this study will utilize standard techniques delivered over 5 to 7 weeks as outlined in the NSABP B-39/RTOG 0413 protocol. PBI will utilize the technologies of high dose-rate multicatheter brachytherapy, high dose-rate single catheter balloon brachytherapy (MammoSite®), and three-dimensional conformal external beam radiation therapy. Ideally, PBI therapy will be given twice a day, at least 6 hours apart, on 5 treatment days over a period of 5 to 10 days and the technique selected will depend on technical considerations, radiation oncology facility technique credentialing, as well as patient preference. Patients randomized to WBI will receive chemotherapy, if applicable, before their radiation therapy. Patients randomized to PBI will receive radiation therapy before chemotherapy, if applicable.

WHOLE BREAST IRRADIATION – GROUP 1

The intent of WBI is to treat the entire ipsilateral breast through tangential fields and ensure that the lumpectomy cavity is dosimetrically covered within the irradiated volume.

If the patient is not receiving chemotherapy, WBI is to be initiated within 9 weeks following lumpectomy or re-excision of margins and within 3 weeks following study entry. For patients receiving chemotherapy, WBI is to begin no fewer than 2 weeks and no more than 8 weeks after the last cycle of chemotherapy.

 Whole breast dose: Acceptable dose to the WBI prescription point/volume is either 50 Gy in 2 Gy per day fractionation or 50.4 Gy in 1.8 Gy per day fractionation, 5 days per week.

 Boost therapy by either photons or electrons to the lumpectomy cavity plus margin is permitted but not required. Brachytherapy boosts are NOT allowed. The boost technique is left to the discretion of the radiation oncologist, but accurate targeting/planning is encouraged.  Boost dose to the prescription point/volume is to be between 10-16.2 Gy at 1.8-2.0 Gy/fraction. Maximal permitted cumulative prescription dose to the lumpectomy cavity plus margin is 66.6 Gy.

Tangential fields: The borders for the tangent fields are set so that they include the targeted clinical breast volume determined above plus a 1–2 cm margin. Examples of typical clinical boundaries for tangent fields are: Medial: usually midsternum. Lateral: usually midaxillary line. Caudad: 1-2 cm below the inframammary line. Cephalad: commonly at the base of the clavicle heads or the sternal manubrium joint

Constraints for critical non-target organs: The perpendicular distance from the chest wall to the posterior field edge can include at maximum 3 cm of lung tissue at any point along the length of the tangent on a film, or a digitally reconstructed radiograph (DRR) of the field. For left-sided cancers, field arrangements that minimize inclusion of the heart in the field should be used.

PARTIAL BREAST IRRADIATION (PBI) BY MAMMOSITE®

Target volumes

The excision cavity will be outlined based either on clear visualization on CT, or if placed, with the help of surgical clips. If the excision cavity cannot be clearly delineated, the patient is not eligible for study participation. As the implanted balloon moves with the target, compensation for variability of treatment set-up and breathing motion is not needed, and therefore, the CTV equals both the PTV and the PTV_EVAL. The targeted breast tissue immediately surrounds the balloon to a measured 10 mm distance from the balloon surface. The PTV_EVAL will be delineated as the breast tissue volume bounded by the uniform expansion of the balloon radius in all dimensions by 10 mm less the balloon volume. However, the PTV_EVAL will be limited to 5 mm from the skin surface and by the posterior breast tissue extent (chest wall and pectoralis muscles are not to be included). When determining dose coverage of the PTV_EVAL to assure compliance with dose requirements as outlined in Section 13.2, the volume of trapped air/fluid must be accounted for as it displaces a percentage of the target beyond 1 cm from the balloon surface. The area of trapped air/fluid will be contoured at each level, a total volume obtained, and the percentage of the PTV_EVAL that is displaced will be calculated. This calculation is illustrated in the following equation: (% PTV_EVAL coverage) – [(vol trapped air/vol PTV_EVAL) x 100] = ≥ 90% When determining the PTV_EVAL dose coverage, this displaced percentage must be subtracted. For example, if the percentage of PTV_EVAL displaced by trapped air/fluid is calculated to be 5%, then to comply with criteria, the dose coverage must be at least 95% of the PTV_EVAL receiving 90% of the prescribed dose. If the percentage of PTV_EVAL displaced by trapped air/fluid is > 10%, then it is not possible to achieve acceptable dose coverage. (See

• Tissue-balloon conformance – Ideally, the lumpectomy cavity surface should be in direct contact with the entire balloon surface assuring maximum prescription dose coverage of the PTV. Frequently air and/or fluid will be identified between the lumpectomy cavity and balloon surfaces. Whether as a result of an irregular cavity shape or because the air/fluid is trapped, this will result in less than ideal conformance as it "pushes" a percentage of the PTV beyond the prescription isodose line coverage. To determine the significance of the trapped air/fluid, these volumes will be contoured and used in calculating PTV_EVAL dose coverage (see Section 13.1.3). Typically when the volume of trapped air/fluid is < 10% of the PTV_EVAL, acceptable dose coverage can be achieved.

• Balloon symmetry – Disruption of the contour of the balloon surface or shifting of the central catheter will cause distortion of the balloon geometry and a negative effect on the dosimetric coverage of the PTV. The physical geometry of the balloon device will not deviate > 2 mm of the expected dimensions.

• Minimal balloon surface-skin distance – Ideally, the minimal balloon surface-skin distance should be ≥ 7 mm. However, if the balloon-skin thickness is 5 mm to 7 mm, then it will be considered acceptable for treatment after appropriate treatment planning documents that the maximum skin dose at any point is ≤ 145% of prescription dose, assuring that the skin dose does not exceed acceptable limits.

• Normal breast tissue dose volume parameters – To assure that acceptable dose homogeneity is not exceeded while striving to achieve target coverage, the volume of tissue receiving higher doses will be limited. The actual volume of tissue receiving 150% (V150) and 200% (V200) of the prescribed dose will be limited to ≤ 50 cc and ≤ 10 cc, respectively. (V150 will be the volume of tissue receiving 150% of the prescribed dose, and V100 will be the volume of tissue receiving the prescribed dose.)

• Treatment utilizing MammoSite® will begin within 9 weeks following lumpectomy or re-excision of margins and within 3 weeks of study entry. A total of 34 Gy will be prescribed to an approximate 1 cm radial distance from the balloon surface such that the dosimetric requirements in Section 13.2 are satisfied. Two fractions per day, each of 3.4 Gy, separated by at least 6 hours, given on 5 treatment days (over a period of 5 to 10 days), will sum to 10 fractions and 34 Gy.

Dose limitations for normal tissues: Uninvolved normal breast: Ideally, < 60% of the whole breast reference volume should receive ≥ 50% of the prescribed dose. For these calculations, the whole breast reference volume is defined in Appendix F. The balloon volume should be subtracted from the whole breast volume for this calculation.

Treatment verification: To assure continued integrity of the balloon throughout treatment, an ultrasound or x-ray must be performed prior to each delivered fraction and evaluated for any change in balloon diameter. These should be compared to a similar study performed at the time of treatment planning. If a change in balloon geometry is noted, this should be addressed prior to additional treatment. If the balloon deflates, it should be removed, a new balloon inserted and reinflated to previous volume, appropriateness for treatment confirmed, and treatment completed.

PARTIAL BREAST IRRADIATION (PBI) BY 3D CONFORMAL EXTERNAL BEAM

The pre-randomization CT data set can be used for 3D-CRT treatment planning. Treatment will be delivered only to the planning target volume (PTV) using 3-dimensional conformal fields. Field within a field technique to improve dosimetric coverage can be utilized; however, the use of dynamic multi-leaf collimator (MLC) to facilitate the delivery of intensity-modulated distributions derived from constraints-based computer optimization (i.e., inverse planning) is excluded. Field arrangements are at the discretion of the physician and will be determined by 3D-CRT treatment planning to produce the optimal conformal plan in accordance with volume definitions. The treatment plan used for each patient will be based on analysis of the volumetric dose including dose-volume histogram (DVH) analyses of the planning target volume for evaluation (PTV_EVAL) and critical normal tissues. Dose calculations with tissue inhomogeneity correction must be used.

Target volumes: The excision cavity will be outlined based either on clear visualization on CT or, if placed, with the help of surgical clips. If the excision cavity cannot be clearly delineated, the patient is not eligible for study participation. The CTV will be defined by uniformly expanding the excision cavity volume by 15 mm. However, the CTV will be limited to 5 mm from the skin surface and by the posterior breast tissue extent (chest wall and pectoralis muscles are not to be included). The PTV, defined as a uniform 10 mm expansion of the CTV, will provide a margin around the CTV to compensate for the variability of treatment set-up and motion of the breast with breathing. The PTV is saved and is used to generate the beam aperture with an additional margin to take penumbra into account. Since a substantial part of the PTV often extends outside the patient (especially for superficial cavities), the PTV is then copied to a PTV_EVAL, which is edited. This PTV_EVAL is limited to exclude the part outside the ipsilateral breast and the first 5 mm of tissue under the skin (in order to remove most of the build up region for the DVH analysis) and excluding (if applicable) the PTV expansion beyond the posterior extent of breast tissue (chest wall, pectoralis muscles and lung). T\

Typically, a 3, 4, or 5-field non-coplanar beam arrangement utilizing high-energy photons can be used. No plan will be considered acceptable if any of the beams are directed towards critical normal structures: heart, lung, contralateral breast.  Bolus to improve anterior target coverage should not be used. 3D-CRT will begin within 9 weeks of lumpectomy or re-excision of margins and within 3 weeks of study entry. A total of 38.5 Gy will be prescribed to the ICRU 50 reference point dose (usually isocenter). Two fractions per day, each of 3.85 Gy, separated by at least 6 hours, given on 5 treatment days (over a period of 5 to 10 days), will sum to 10 fractions and 38.5 Gy.

Dose limitations for normal tissues: Uninvolved normal breast: Ideally, < 60% of the whole breast reference volume should receive ≥ 50% of the prescribed dose and < 35% of the whole breast reference volume should receive the prescribed dose. For these calculations, the whole breast reference volume is defined as per Appendix F. Contralateral breast: The contralateral breast reference volume, contoured using the same methods described for the ipsilateral breast reference volume, should receive < 3% of the prescribed dose to any point. Ipsilateral lung: < 15% of the lung can receive 30% of the prescribed dose. Contralateral lung: < 15% of the lung can receive 5% of the prescribed dose. Heart (right-sided lesions): < 5% of the heart should receive 5% of the prescribed dose. Heart (left-sided lesions): The volume of the heart receiving 5% of the prescribed dose (V5) should be less than the 40%. Thyroid: maximum point dose of 3% of the prescribed dose.

Group 2 patients (PBI). Adjuvant chemotherapy will be given following PBI. Chemotherapy will be initiated no sooner than 2 weeks after the completion of PBI.