APBI: 27Gy in 5 Fractions for Early Breast Cancer

This study will test the safety of partial breast RT using 27Gy in 5 daily fractions which is expected to be equally tolerated as standard whole breast irradiation (WBI) based on radiobiologic modeling of the fibrosis response of normal tissues but be more convenient and less costly than 3-6 weeks of standard WBI. 274 women will be treated. Rates of fibrosis and cosmesis at 2 years will be compared to data already collected using standard WBI in the Canadian RAPID trial.

Background: Previously, accelerated partial breast irradiation (APBI) using 3D conformal external beam techniques to deliver 38.5Gy in 10, twice daily, fractions caused worse fibrosis and cosmetic deterioration than standard whole breast irradiation (WBI) following breast conserving surgery (BCS) for women with early breast cancer. Over the decade since the original APBI technique was designed, long-term outcomes of various breast RT fractionation regimens have become available and suggest that normal tissue fibrosis and cosmesis varies with the radiobiological constant: α/β=2 rather than α/β=3.4 as previously estimated. Radiobiologic modeling using α/β=2, indicates that a dose of 27Gy in 5 daily treatments should result in comparable late effects as 42.5Gy in 16, or 50Gy in 25 fractions. This clinical trial will validate the safety of a short, convenient and less costly APBI using 27Gy in 5 daily fractions.

Objective: To determine the cosmetic and normal tissue outcomes of APBI using 3D-conformal RT with 27Gy in 5 fractions over 1 week.

Methods: A single-arm, phase II, non-inferiority, prospective study will be conducted. 274 women with newly diagnosed, invasive or in-situ ductal carcinoma treated with BCS and sentinel lymph node biopsy (or axillary dissection) who are candidates for WBI alone, will be treated. Subjects will be age 50 years and older, with tumors less than 3cm diameter, with negative margins and nodes and with excellent or good baseline cosmetic outcome following BCS. Patients with extensive ductal carcinoma in-situ, BRCA mutations, Grade 3 cancers with lymphatic or vascular invasion, or lobular carcinoma will be excluded. These selection criteria are similar to the Canadian RAPID trial. In the first phase of the study, 150 patients will be recruited and interim analyses will be conducted to rule out unacceptable toxicity at 2 years.

Study endpoints: The primary endpoint will be the proportion of women who retain an Excellent or Good cosmetic score at 2 years using the EORTC Cosmetic Rating System and clinical photographs taken prior to, and at 1 and 2 years after RT. Secondary endpoints will include rates and grades of breast fibrosis, induration, telangiectasia, breast pain, ipsilateral breast tumor recurrence, overall and breast cancer-specific survival and subsequent mastectomy rates.

Sample size, statistical analyses: In the RAPID trial, 88% of patients with Excellent or Good cosmesis prior to RT had Excellent or Good scores at 3 years. Only patients with Excellent/Good cosmesis at baseline will be included in the current study. The proportion of women with Excellent/Good cosmesis at 1 and 2 years will be calculated. Using 80% power, a non-inferiority margin of 0.08 and a one-sided binomial test for non-inferiority and a significance level of 0.05, will require a sample size of 249 women with evaluable 2-yr cosmesis. 274 patients will be recruited to allow for a 10% drop-out rate. To ensure safety, a first interim analysis with Grade 2 or higher breast fibrosis as the primary endpoint, will be conducted when 50 patients have completed their 1-year assessment and repeated when 50 patients have completed their 2-year follow up. If the rate of Grade 2 or higher fibrosis exceeds 5% at either time point, trial accrual will be suspended.

Feasibility: Over 600 women eligible for this protocol receive RT in Alberta each year. If 30% accept study participation, accrual will be complete in \<2 years.

Eligibility Criteria:
Inclusion Criteria:

* Female, with new invasive or in-situ ductal carcinoma of the breast
* Treated with Breast conserving surgery (BCS) with negative margins
* pN0 on sentinel node biopsy or axillary dissection; cN0 if DCIS alone
* Maximum pathologic tumor diameter is 3.0 cm (invasive or DCIS)
* No clinical or imaging evidence of distant metastases
* Age 50 years or older at diagnosis
* No contraindications to breast irradiation
* Excellent or Good overall cosmetic score at baseline following BCS
* Able and willing to provide written informed consent
* Available for 2 year follow up at the treating RT centre

Exclusion Criteria:

* Age \< 50 years at diagnosis
* BRCA 1 or 2 pathogenic mutation
* Pathologic tumor diameter \>3cm (including DCIS+invasive disease)
* Lobular histology alone
* Triple negative (ER-, PR-, HER2-) or HER2 overexpressing disease
* Margin (other than deep) \<2 mm
* Presence of both Grade 3 and lymphatic or vascular invasion
* Fair or Poor overall cosmetic score at baseline following BCS
* Presence of ipsilateral breast implants
* Inability to develop an APBI plan meeting all dosimetry constraints
* Unable to start RT within 16 weeks of BCS or 8 weeks of last iv chemotherapy
* Unable or unwilling to sign informed consent document or attend for 2-year cosmetic assessment at the treating RT centre
* Potential contraindications for breast RT including a confirmed diagnosis of lupus, scleroderma, or pregnancy