Radiation induces bone damages in several ways [20, 21]. Bone irradiation decreases the number of osteoblast, which subsequently decreases collagen production and alkaline phosphatase activity . Since collagen and alkaline phosphatase are crucially involved in the process of bone mineralization, their decrease causes osteopenia . In addition, radiation directly induces atrophic changes in the bone by reducing the amount of calcium and phosphorus . Moreover, radiation causes vascular injuries such as obliterative endarteritis and periarteritis in the bone [20, 23]. These inflammatory changes in the vascular structure can lead to atherosclerosis formation and vessel occlusion, which affects blood flow to the bone [12, 20, 23]. Given these damages, irradiated bones are fragile to the fracture; therefore, in patients with thoracic malignant diseases, follow-up examination after radiotherapy often reveals RIRF [9, 21, 24]. In our study, 18.0% of patients with breast cancer presented with RIRF after adjuvant radiotherapy. The incidence of RIRF in our study was quite higher than that in previous studies on patients with breast cancer, which ranged from 1.0–3.8% [4–6]. However, these previous studies detected RIRF using X-ray or CT scan, and other previous studies using bone scintigraphy to detect RIRF reported an incidence rate of 12.9–18.5%, which is similar to the incidence rate in our study [9, 10, 12]. Since bone scintigraphy has a high sensitivity for detecting fractures and patients with RIRF often lack symptoms, a significant proportion of patients with breast cancer undergoing adjuvant radiotherapy, which could be higher than the expected proportion, might experience RIRF during follow-up without clinical recognition [9, 12].
In our study, multivariate analysis revealed that tumor-rib distance was associated with the risk of RIRF. Regarding postoperative radiotherapy for breast cancer, boost radiotherapy to the tumor bed is commonly administered to most patients who undergo breast-conserving surgery. Furthermore, based on histopathological results, some patients who undergo complete mastectomy may receive boost radiotherapy. Therefore, the tumor bed receives a higher radiation dose than other breast tissue. As mentioned above, the tumor-rib distance was defined as the minimum distance between the tumor margin and rib. In other words, it could be assumed that the shorter the tumor-rib distance, the higher dose is irradiated to the rib, resulting in more RIRF occurrence. In a previous study on patients with breast cancer , boost radiotherapy was not a significant risk factor for RIRF as shown in our study; however, the authors discussed that RIRF could have significant association with the tumor-rib distance. Another previous study on patients who underwent pulmonary hypofractionated stereotactic body radiotherapy reported that a tumor-rib distance less than 2.0 cm was the only significant risk factor for RIRF . Unlike our study, this previous study defined tumor-rib distance as the minimum distance between the radiation isocenter and rib; nonetheless, it also showed that the tumor-rib distance is negatively correlated with the risk of RIRF similar to the results of our study.
Dose-dependent rib volume parameters, including V20, V30, and V40, were significantly correlated with the risk of RIRF in the present study. Several studies have investigated the association of total radiation dose or fraction size with the risk of RIRF [8, 9]. However, to our knowledge, no studies have assessed the association between the risk of RIRF and the absolute rib volume receiving a certain radiation dose of radiation in patients with breast cancer receiving conventional standard radiotherapy. A previous study on lung cancer reported differences in V20, V30, and V40 between fractured and unfractured ribs . Since this previous study investigated hypofractionated stereotactic body radiotherapy, it could not be directly compared with our study. However, it would be suggested that the absolute rib volume receiving a certain radiation dose can affect the RIRF. In a study on patients with breast cancer who underwent accelerated partial breast irradiation, which is a type of hypofractionated radiotherapy for treating partial breast, the RIRF incidence rate was significantly lower (0.5 %) than that in previous studies on whole breast radiotherapy [4, 25]. Although these studies were performed in patient populations receiving hypofractionated radiotherapy, the radiation field size is directly correlated with the irradiated absolute rib volume and the risk of RIRF. Therefore, these results implies that a dose-dependent rib volume can be an important risk factor for RIRF.
To reduce RIRF, it is necessary to consider risk factors for each patient including tumor-rib distance, and, additionally, precision radiotherapy techniques that allow reduction of the dose-dependent rib volume should be performed for patients at a high risk of RIRF incidence. Among them, one of the approaches for reducing the irradiation dose to the rib is radiotherapy in a prone, rather than supine, position. Treatment in a prone position allows the breast tissue to sag down, which increases the tumor-rib distance, and, additionally, a prone position reduces the absolute rib volume receiving a certain radiation dose. Notably, a study of patients who underwent breast radiotherapy in the prone position reported no RIRF occurrence . However, a prone position is less effective for chest wall irradiation in patients without remnant breast tissue and is unsuitable for treating advanced-stage patients requiring the inclusion of regional lymph nodes. Therefore, the prone position could be selectively applied to early-stage patients and relatively large breast sizes.
The deep-inspiration breath-hold (DIBH) technique is another method for reducing the irradiation dose to the ribs. To our knowledge, no study have assessed the RIRF incidence in patients with breast cancer treated using the DIBH technique. However, DIBH is known to reduce the irradiated dose to the ipsilateral lung through chest wall expansion [27–29]. Since the ipsilateral lung is located just behind the ribs, the reduced irradiated dose to the lung suggests a decreased irradiated dose to the ribs. In addition, when the chest wall expands, the rib spacing widens; however, the treatment target does not significantly change; accordingly, there is an expected reduction in the rib volume affected by radiation at a specific dose. In the previous studies [27, 28], the dose to the ipsilateral lung was more effectively reduced in patients treated with regional lymph node irradiation. This could allow dose reduction to ribs in radiotherapy for patients with advanced-stage breast cancer. Future studies that investigate the clinical role of DIBH for reducing RIRF in patients with breast cancer are required.
This study had some limitations. First, this was a single-center retrospective study, which might have led to selection bias. Second, since the diagnosis of RIRF was determined using bone scintigraphy and follow-up imaging examinations, the incidence of RIRF in our study could have been overestimated .