Is there a worthwhile value in personalizing radiation therapy for breast cancer patients? Time for a new paradigm in the older adult population

Over the past few decades, the world population has increased dramatically including a large number of elderly people. This explosion in population aging comes with a rising number of older adults who have potential multiple comorbidities and chronic illnesses, including cancer. Indeed, the prevalence of multimorbidity in older patients ranges from 55 to 98% [1]. Older cancer population represents a major public health issue and tailoring of treatment for these patients represents a paradigmatic example of treatment optimization. The number of elderly living with cancer disease is high due to the possibility of early diagnosis in the last years and the recent advances in cancer treatment strategy. Breast cancer is the most common malignancy among women, and it is estimated that around 20% of newly diagnosed patients will be aged more than 70 years. It has been widely reported that breast cancer-related mortality increases with age, regardless of disease stage. A specific management for this elder population is not defined because clinical trials usually do not include this subset of patients. The International Society of Geriatric Oncology in conjunction with the European Society of Breast Cancer Specialists recommended that any decision to treat cancer in the older adult woman with cancer must be individual and based on specific evaluation of the elderly woman and cancer. Physiological age, life expectancy, treatment tolerance, patient preference, potential barriers to the proposed treatments, competitive causes of mortality, and broad geriatric evaluation must be deeply considered [2]. Many investigators are recently focusing their efforts on optimization of cancer treatment strategy in older patients. With this regard, the ongoing COVID-19 pandemic has reinforced the urgent need also to minimize exposure of our patients to virus without compromising oncological outcome [3]. Currently, the standard of care for most patients affected by early invasive breast cancer still remains whole breast irradiation (WBI) after breastconserving surgery (BCS), since WBI showed a decrease in first recurrence also in low-risk elderly patients, with a lower absolute 10-year risk reduction of any locoregional or distant relapse [4,5]. The randomized CALGB 9343 trial evaluating 636 patients aged more than 70 years affected by invasive breast cancer treated with BCS and adjuvant tamoxifen with or without postoperative WBI demonstrated a significant decrease in the local relapse rate in favor of the group of patients receiving postoperative radiation therapy (RT) [6]. Shorter courses using moderate hypofractionated schedules should currently represent the standard of care for WBI, since a level-1 evidence exists on equivalent local control and late toxicity rates [7]. A brand-new approach to optimization of RT is the ultra-hypofractionated schedule given over just oneweek, feasible option in selected low-risk patients. The FAST Forward trial compared 26 Gy or 27 Gy in 5 fractions over 1 week to 40 Gy in 15 fractions over 3 weeks. At 5 years, the two experimental regimens were shown to be non-inferior to 40 Gy with respect to local recurrence in the breast, with a safety profile in favor of 26 Gy in 5 fractions as compared to a total dose of 27 Gy [8]. Among the available strategies to de-escalate RT, the omission of the tumor bed boost has been widely investigated and currently represent a viable option for most of patients affected by breast cancer in the elderly. Several studies compared RT with or without a tumor bed boost over the last decades (Table 1) [9–12]. Results from the aforementioned trials highlighted the benefit of addition of boost on local relapse rates, without any impact on survival outcomes. This advantage decreases with increasing of age and should be carefully assessed, considering also the augmented risk of late adverse effects, such as fibrosis. Based on the current guidelines, the omission of bed boost is advised for most patients aged more than 60 years, with positive hormonal receptor status, low-grade tumors and negative surgical margins. An additional de-escalating approach in older women is represented by partial breast irradiation (PBI), combining shorter overall duration of treatment and smaller target volumes. This strategy has been investigated in several large phase III trials (Table 1) [13–19]. The European Society for Radiotherapy and Oncology (ESTRO) [20] and the American Society for Radiotherapy and Oncology (ASTRO) recommendations [21] defined a specific age cutoff for delivering PBI,