Breast cancer is a prevalent form of cancer and one of the leading causes of death among women worldwide. The World Health Organization (WHO) reports that breast cancer is the most commonly diagnosed cancer among women globally, with an estimated 2.3 million new cases in 2020. In the United States, breast cancer accounts for approximately 30% of all new female cancer diagnoses annually, and it is projected that 43,700 women will die from breast cancer in 20232. Despite advancements in diagnosis and treatment, breast cancer remains a significant public health concern. Breast cancer can be effectively treated with radiotherapy, which involves using high-energy radiation to destroy cancer cells and prevent their growth and spread. However, as radiation transmission in matter cannot be precisely controlled, it can affect healthy cells, particularly those near cancer cells. Therefore, an optimal treatment plan should aim to maximize the impact of radiation on the cancerous tissue while minimizing its effects on healthy tissues.

The radiotherapy technique is a critical factor in achieving an effective breast cancer treatment plan. Modern devices, such as the Halcyon system (1), that utilize intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT), provide a simpler way to achieve this compared to less modern devices with fixed radiation beams. The Halcyon offers several advantages over a conventional LINAC in the context of treatment planning. With its single 6 MV flattening filter-free (FFF) X-ray, the Halcyon system delivers a higher dose rate, leading to faster treatment sessions and improved patient comfort. The double-layer multi-leaf collimator (MLC) enables precise beam shaping, enhancing target conformity and sparing surrounding healthy tissues. Additionally, the Halcyon’s faster gantry rotation speed and maximum leaf speed contribute to reduced treatment times, increasing treatment efficiency and minimizing motion-related uncertainties. These combined features make the Halcyon LINAC a particularly choice for treatment planning, ensuring better dose delivery and overall treatment outcomes compared to conventional LINACs. However, given a specific radiotherapy technique, there are various treatment plans that can be constructed, with the total dose and number of treatment fractions being significant parameters. A conventional fractionated (CF) treatment plan for breast cancer typically involves a total dose of 50 Gy administered over 25 treatment fractions. The extended duration of the CF plan limits the capacity to treat a larger number of patients, particularly in developing countries such as Vietnam. Moreover, the cost and travel distance to the radio-therapy center for several weeks can cause financial difficulties for patients. There has been a trend towards using a hypo-fractionated (HF) plan, which has a shorter treatment duration than the CF plan. Although the total dose and number of treatment fractions are lower in an HF plan, the dosage per fraction is higher than that of the CF plan. This trend is evident in the review of Yasemin Bolukbasi and Ugur Selek (2), and studies have confirmed that the HF plan is safe and effective (3–6), yet some inconsistent results exist. For instance, Arezoo Kazemzadeh et al (7) used radiobiological models and found that the tumor control probability and equivalent uniform dose of the CF plan were better than those of the HF plan, contradicting the conclusion of Gloi (8). The review of Youssef and Stanford (9) added that “breast fibrosis can be a potential side effect of hypofractionated radiotherapy”. Additionally, there is no standard value for the HF treatment plan, necessitating further research to understand the differences in effectiveness between CF and HF treatment plans. The findings from these studies, as well as the dosimetric data collected, can help to explore more intensified hypofractionated treatment plans, with initial results indicating comparable effectiveness between the plan of 28.5 Gy in 5 fractions and the standard plan of 50 Gy in 25 fractions (10). While the Halcyon system is a state-of-the-art linear accelerator that provides high-quality IMRT and VMAT treatments, there are a limited number of studies on this specific machine. Therefore, the purpose of this study is to evaluate the efficacy of two breast cancer treatment plans based on the Halcyon system using two radiobiological models: the CF plan, which delivers a total dose of 50 Gy over 25 treatment fractions, and the HF plan, which delivers a total dose of 42.56 Gy over 16 treatment fractions.

It is worthy to note that at our hospital, we currently adhere to the National Comprehensive Cancer Network (NCCN) Guideline for treating breast cancer patients (11). In radiation therapy practice, we routinely accept both CF and HF plans according to the NRG Radiation Therapy Oncology Group (RTOG) Template for whole breast photon therapy (12–14). The final decision of which plan should be used in a given case is almost random. This is acceptable because both plans adapt the mandatory requirements of safety, nevertheless we aim to find out which plan.

As described in section 2.1, CF and HF plans are applied to two separate groups of patients. To compare the effectiveness of the CF and HF plans, it is important to ensure that the two groups of patients have similar characteristics. However, in this study which only considered DVH data, it is only necessary to ensure that the organs being treated are anatomically comparable between the two groups. Other demographic factors, such as age and gender, do not affect the analysis. Figure 1 shows a boxplot to visually compare the size of organs of the two groups of patients. It is seen that the sizes of the organs of these two groups are comparable. This observation is confirmed with the t-test comparison given in Table 2 . It is displayed that all the t-values are nearly zero except for the heart. The high t-value corresponding to the heart might be due to the bias of an outlier data point as can be seen in Figure 1 . In fact, it may be preferable in a planning study to simulate both treatments in each patient, as this enables a paired comparison and even a voxel-by-voxel comparison of physical dose, and thus eliminates the need to determine whether the groups are comparable. However, a study based on actually delivered plans, such as the one presented here, has its own advantage in that it provides insight into the practical clinical experience, including the occurrence of any adverse effects. For this reason, a similar strategy was also carried out by many other works, see e.g., Refs (5, 7, 8, 21).

Table 3 presents a comparison of the CI, HI, EUD, TCP, and NTCP values of CF and HF plans using an independent sample t-test. The results show that both treatment plans have a high CI value (>0.95), indicating that they effectively concentrate radiation dose within the PTV, i.e., the cancerous breast, while minimizing exposure to healthy tissues. This is an important aspect of radiation therapy, as it reduces the likelihood of side effects and complications. The results suggest that both treatment plans are well-suited for treating breast cancer patients using the Halcyon system. A comparison with prior research demonstrates that the CI value is independent of the treatment plan, Refs (9, 10) also revealing nearly identical CI values for the CF and HF treatment plans. Indeed, a high value of CI can be attained through enhanced therapy methods. For example, the CF plan combined with the IMRT and VMAT treatment techniques in our work yields a CI value of 0.96, whereas the same treatment plan with the 3D-CRT technique in the work of Kazemzadeh A et al. (9) yields only 0.89.

When the HI values are compared, the CF plan does a little better than the HF plan. This means that the CF plan was able to spread the radiation dose more evenly across the PTV than the HF plan. A uniform distribution of radiation dose is essential, as an uneven dose distribution may cause certain parts of the cancerous organ to receive excessive radiation, while others receive insufficient radiation to effectively destroy the cancerous cells. This can result in incomplete treatment, allowing cancerous cells to survive and recover after the therapy. Therefore, a homogeneous distribution of radiation dose within the PTV is desirable in order to achieve optimal therapeutic outcomes. In general, the HI values of both the CF and HF plans in the present work are fairly good, as they are less than 0.10, indicating that the maximum discrepancy of the dose received at two random locations inside the PTV is less than 10%.

The TCP value of the CF plan, which is 96.0 ± 0.1%, is better than that of the HF, which is 94.0 ± 0.3%, as expressed by the large t-value of 23.67 together with a p-value of almost zero. This result for the TCP value is consistent with that reported in Ref (9). Yet inconsistent with that given in Ref (10), in which the TCP value of the CF plan is lower than the HF plan. We should note that the authors of Ref (10) reported their TCP values with extremely large uncertainty, in contrast to the small uncertainty reported in this study and Ref (9).

The NTCP values for the heart of both CF and HF plans are all extremely close to zero. For the lung, the NTCP values of the HF plan are better than those of the CF. In addition, the NTCP of the ipsilateral lung is 12 times larger than that of the contralateral lung for both treatment plans. It is evident because the ipsilateral lung is located on the same side as the PTV, so it receives a higher dose than the contralateral lung. In general, the CF plan is more effective at controlling tumor growth, as suggested by its better TCP values, yet the HF plan causes fewer side effects and complications for the patients, demonstrated by its better NTCP values, particularly the lung. We should note that this claim is only valid for treatments utilizing IMRT techniques on a Halcyon system, also noting that in the study of Kazemzadeh A et al. (9), in which the treatment were made on an ARTISTE radiation therapy system (SIEMENS) using 3D-CRT technique, the NTCP for the lung of the HF plan was reported to be worse than that of the CF.

For the EUD values, that of the CF plan is higher than that of the HF. This is expected because the total dose of the CF plan is greater than that of the HF case. However, there is an interesting observation that the relative ratio between the EUD and the total dose in the CF plan is lower than in the HF plan. In the CF plan, a total dose of 50 Gy results in a EUD of 52.39 Gy (107%), whereas a 42.56 Gy total dose in the HF plan causes a EUD of 49.14 (114%). A similar effect is seen when comparing V_RI of the CF and HF plans for the PTV and chest wall, as shown in Table 4 . With the same relative reference isodose of 105% with respect to the total dose (i.e., 53.5 Gy versus 50 Gy and 45.53 Gy versus 42.56 Gy), the V_RI value of the CF plan is greater than that of the HF plan, whereas the V_RI values with the relative reference isodoses of 95% and 100% show the contrary. This observation suggests that the HF plan delivers doses to the PTV more effectively than the CF plan. It also implies that the current configuration of the HF plan may not be optimal, and there may exist a treatment plan with a higher EUD, even greater than the EUD obtained from the CF plan. In addition, behaviour of the EUD observed in our work was not shown in Ref (9). Since both works considered the same CF and HF treatment plans but used different treatment techniques, namely IMRT and VMAT in this work versus 3D-CRT in Ref (7), it is possible that the choice of treatment plan varies with the treatment technique.

Overall, the results of the present work suggest that, for the Halcyon system with IMRT technique, the CF plan is better at controlling tumor growth than the HF plan, but the HF plan is better at keeping side effects and complications to a minimum. The HF plan has the additional advantage of a shorter treatment duration. In addition, the analysis of the EUD shows that there might exist a configuration of the HF plan that can provide the same or even a greater EUD value than that of the CF plan. In future studies, we intend to perform a search to find the optimal configuration of the HF plan. Moreover, although all the comparisons in this work are based on a t-test with a replication probability of more than 95%, recalling that we accept the hypothesis only if the p-value is less than 0.05. Further, it is to be acknowledged that the number of samples, 28 patients, is quite small. Therefore, the obtained results must be considered with caution until further studies with a larger sample size are conducted.

In conclusion, this study compared the effectiveness of conventional and hypofractionated radiotherapy treatment plans for breast cancer patients using radiobiological models and analyzed dosimetric parameters. The results suggest that while the CF plan is more effective in tumor control, the HF plan is better at minimizing side effects and complications and has the advantage of a shorter treatment duration. Additionally, the analysis of the EUD suggests that there might be an optimal configuration of the HF plan that can provide the same or even a higher EUD value than that of the CF plan.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

DT: Conceptualization, Data curation, Methodology, Project administration, Software, Supervision, Validation, Writing – original draft, Writing – review & editing. LT: Conceptualization, Data curation, Methodology, Software, Writing – original draft. NN: Conceptualization, Methodology, Software, Writing – original draft. HS: Data curation, Writing – original draft. TL: Data curation, Writing – original draft. XN: Conceptualization, Investigation, Writing – original draft, Writing – review & editing. PS: Conceptualization, Writing – original draft, Writing – review & editing. DB: Investigation, Supervision, Writing – review & editing. JC: Conceptualization, Investigation, Project administration, Writing – original draft, Writing – review & editing.