PRISM Trial: Partial Breast Versus Whole Breast Radiation in Early Breast Cancer

Breast Cancer (BC) is the most common malignancy among women worldwide and represents a significant and growing health burden in Low- and Middle-Income Countries (LMICs), including Pakistan. According to GLOBOCAN (2022), approximately 2.3 million women were diagnosed with breast cancer globally, with nearly 670,000 deaths reported. Asia alone accounted for nearly 1 million new cases, representing 42.9% of the global burden.

Breast-Conserving Surgery (BCS) followed by Whole Breast Irradiation (WBI) remains the standard treatment for women with early-stage breast cancer. Recent advances in radiotherapy have demonstrated that ultra-hypofractionated WBI, delivered as 26 Gy in five fractions, provides comparable tumor control with reduced treatment duration and improved patient convenience. Partial Breast Irradiation (PBI) has also emerged as an attractive alternative by limiting radiation exposure to the tumor bed and surrounding tissues, thereby potentially reducing treatment-related toxicity while maintaining excellent oncologic outcomes in appropriately selected patients. Multiple randomized trials have demonstrated that PBI provides oncologic outcomes comparable to WBI in appropriately selected patients, with similar rates of ipsilateral breast tumor recurrence (IBTR). A meta-analysis of 14 randomized and observational studies involving over 17,000 patients reported comparable 5-year (RR 1.34) and 10-year (RR 1.29) IBTR rates between PBI and WBI, with reduced acute toxicity and similar late toxicity. The RAPID trial, a multi-center randomized study of 2,135 women, demonstrated non-inferior local recurrence rates at 8 years (3.0% vs. 2.8%) using PBI (38.5 Gy in 10 twice-daily fractions) compared with WBI; however, PBI was associated with significantly higher late toxicity and poorer cosmetic outcomes, with increased grade 1-2 toxicities and adverse cosmesis at 3 years. These findings were largely attributed to the twice-daily treatment schedule and shortened 6-hour interfraction interval, which may have limited normal tissue repair. This hypothesis was supported by evidence from head and neck radiotherapy demonstrating increased toxicity with shorter interfraction intervals. Subsequently, the Canadian phase II OPAR trial evaluated once-daily PBI (27.5 Gy or 30 Gy in 5 fractions) and demonstrated excellent cosmetic outcomes, low toxicity, and only three local recurrences at a median follow-up of 3.1 years, supporting once-daily PBI as a safer and more tolerable approach.

Further evidence from the IMPORT LOW trial (40 Gy in 15 fractions) and the Florence trial (30 Gy in 5 fractions delivered on alternate days) confirmed that appropriately delivered PBI achieves comparable local control to WBI while reducing acute and late toxicity and improving cosmetic outcomes. Similar findings have also been reported in the GEC-ESTRO and TARGIT-A trials, further supporting the oncologic safety of PBI in selected patients. In addition to reducing irradiated breast volume, PBI may decrease radiation exposure to critical organs such as the heart, potentially lowering the long-term risk of ischemic heart disease associated with WBI. Despite these encouraging results, important limitations remain, including heterogeneity in dose, fractionation, target delineation, and treatment techniques across studies, limited long-term follow-up for some PBI regimens, and the use of conventional rather than contemporary hypofractionated WBI as the comparator in many trials. Moreover, previous studies have primarily focused on local control and cosmesis, with limited evaluation of dosimetric parameters and their correlation with clinical outcomes, highlighting an important gap that warrants further investigation.

Furthermore, there is no prospective evidence directly comparing ultra-hypofractionated PBI and WBI using the same dose schedule and modern Intensity-Modulated Radiotherapy (IMRT) techniques. The PRISM trial aims to address this evidence gap by comparing toxicity, dosimetric parameters, and early oncologic outcomes between these two treatment approaches.

The primary objective of this study is to compare the incidence and severity of acute radiation-induced skin toxicity between patients receiving ultra-hypofractionated WBI and those receiving ultra-hypofractionated PBI.

Secondary objectives include comparing early late toxicity up to 12 months, evaluating dosimetric parameters, estimating Normal Tissue Complication Probability (NTCP), correlating dosimetric parameters with observed toxicity, and assessing intermediate oncologic outcomes including overall survival and breast cancer-specific survival.

Inclusion criteria

• Women aged ≥45 years.
• Newly diagnosed, histologically confirmed breast carcinoma, including Invasive Ductal Carcinoma (IDC), Invasive Lobular Carcinoma (ILC), or Ductal Carcinoma in Situ (DCIS).
• Early-stage disease (T1-T2, node-negative [N0]), with no evidence of distant metastasis.
• Hormone receptor-positive disease (ER and/or PR positive).
• HER2-positive disease, provided patients have received or are receiving appropriate HER2-targeted therapy, as per institutional practice.
• Patients who have undergone breast-conserving surgery with no tumor on inked margins or no residual disease following re-excision.

Exclusion criteria

• Age <45 years.
• Multicentric disease.
• Locally advanced or node-positive disease (T3-T4 and/or N+) or evidence of distant metastasis.
• Lobular Carcinoma In Situ (LCIS).
• Triple-negative breast cancer.
• Positive surgical margins or incomplete breast-conserving surgery not suitable for re-excision.
• Prior ipsilateral breast irradiation.
• Non-breast malignancy within the past 5 years, except treated non-melanoma skin cancer or in-situ carcinoma.
• Pregnancy or lactation at enrollment.
• Inability to identify the tumor bed on planning Computed Tomography (CT), such as absence of surgical clips or seroma.
• Unacceptable radiotherapy planning feasibility for the experimental technique according to protocol constraints.