Cervical cancer (CC) is a major cause of morbidity and mortality among women, with approximately 604,000 newly diagnosed cases and 342,000 deaths in 2020 (1). Brachytherapy plays a critical role in the treatment of locally advanced CC, providing significant benefits for the improved pelvic control and overall survival (2). The efficacy of brachytherapy is largely associated with the total doses and dose per fraction, which may induce short and long term injury to normal tissues. The American Brachytherapy Society has recommended that brachytherapy with doses ranging from 4 to 8 Gy per fraction, administered in 4 to 8 fractions, is feasible in clinical practice (3). In accordance with the current guidelines and recommendations, several dose-fractionation schedules, such as 30 Gy in 5 fractions (6 Gy × 5 F) and 28 Gy in 4 fractions (7 Gy × 4 F), have been widely used in brachytherapy. However, there is a lack of consensus in the choice of dose-fractionation schedule considering the current workflow. Indeed, a variety of the schedules are practiced in different institutions, and even within the same institution, variations exist due to different opinions of physicians (4–14). Therefore, there is a need to find a better schedule that allows reducing normal tissue complications without compromising local control of the disease among the schedules commonly used in clinical practice.

In most of the existing studies, the prescribed dose refers to the dose at point A, which is the point located at 2 cm lateral to the central canal of the uterus and 2 cm from the mucous membrane of the lateral fornix in the axis of the uterus (15). However, this approach is not suitable for tumors that are too large, too small, or irregularly shaped, and the prescribed dose at point A cannot correctly represent the dose received by the tumors. Furthermore, this can also increase the dose received in the organs-at-risk (OARs), such as the rectum (16). Dose assessment of tumors and OARs in image-guided adaptive brachytherapy (IGABT) has gradually changed from point dose to dose-volume parameters, thereby improving the accuracy of dose assessment and the underlying treatment (17–19). In our institution, three dose-fractionation schedules are routinely used in brachytherapy, based on the dose-volume parameters. Therefore, the aim of this study was to provide clinical evidence for the selection of dose-fractionation schedules in IGABT, by comparing the differences between the three schedules in terms of dosimetric parameters, therapeutic efficacy, and late toxicities.

The study protocol was approved by the medical research ethical committee of our institutional review board. Written informed consent was waived, considering the retrospective nature of this study that the entire analysis was based on existing clinical data, and did not interfere with the current clinical workstream.

The detailed information of patient characteristics is presented in Table 1 . Among the 45 patients included in this study, a total of 225 brachytherapy plans were analyzed, comprising 90 plans in Group-5.5, 75 plans in Group-6.0, and 60 plans in Group-7.0. There were no significant differences in terms of the patient’s age, staging, hemoglobin level, squamous cell carcinoma antigen level, volume of HR-CTV at the first time of brachytherapy, the overall treatment time, the proportion of intracavitary/interstitial brachytherapy, and the number of needles used in brachytherapy, between the three groups (all P > 0.05).

High-dose-rate brachytherapy is characterized by a shorter treatment duration and reduced occupational radiation exposure for medical staff. It has been shown to provide comparable or even superior outcomes compared to low-dose-rate brachytherapy (22, 23). Dose-fractionation schedules for brachytherapy vary significantly among different centers, and the optimal schedule is still a subject of debate (4–14). Therefore, our study aimed to investigate the dose-response relationships of different IGABT fractionation schedules in the treatment of uterine cervix carcinoma. In this study, although Group-5.5 achieved the highest HR-CTV and IR-CTV doses, it also exhibited the highest OAR doses in terms of bladder and rectum, thus resulting in poor clinical outcomes. Contrarily, Group-6.0 yielded a relatively high HR-CTV and IR-CTV doses with low OARs doses, providing the most beneficial clinical outcomes in brachytherapy for cervical cancer.

The study results revealed no significant positive correlation between the CR rate and the HR-CTV received dose during brachytherapy. For HR-CTV, the EQD₂ corresponding to the brachytherapy dose of Group-5.5 was significantly higher than that of Group-6.0 and Group-7.0. However, in regard to the clinical therapeutic effects, the CR rate of Group-5.5 was lower than the CR rates of the other two groups. Even though the HR-CTV dose of Group-7.0 was the lowest, the CR rate of Group-7.0 was higher than that of Group-5.5. The lowest CR rate in Group-5.5 may be contributed by the longer overall treatment time compared to the other two groups. In the present study, the overall treatment time in Group-5.5, Group-6.0 and Group-7.0 was 59.47 ± 3.58, 56.40 ± 3.6 and 55.20 ± 6.74 days, respectively. Previous data show that patients were exposed with a 2.4-fold risk of local recurrence, and their local control rate decreased by 0.63% for each day, when the total treatment duration exceeded 8 weeks (24). Our findings aligned with these conclusions. It should be noted that the doses and numbers of fractions used in the three different dose-fractionation schedules (e.g., 5.5 Gy × 6 F, 6.0 Gy × 5 F, and 7.0 Gy × 4 F) in this study were all within the recommended range of ABS.

The dose of brachytherapy is determined by both the prescribed dose and the number of fractions. Generally, late-responding tissues tend to be more sensitive to the prescribed dose. A study by Patel et al. compared two dose-fractionation schedules, 9 Gy × 2 F (Arm A) and 6.8 Gy × 3 F (Arm B), revealing that the 3-year actuarial risks of developing Grade 3 and above toxicity in Arm A and Arm B were 7.47% and 3.57%, respectively (25). Similarly, Wang et al. demonstrated that the incidence of proctitis in the patients with 7.3 Gy × 3 F was higher than that of the patients with 4.8 Gy × 5 F (11); and this result is consistent with our finding that the incidence of radiation cystitis in Group-7.0 was higher than that in Group-6.0 (60.00% vs. 46.67%). At the same time, the incidence of radiation proctitis in Group-7.0 was higher than that in Group-6.0 (33.33% vs. 20.00%), and even one case developed Grade 4 radiation proctitis in Group-7.0. However, Le Pechoux et al. compared the dose-fractionation schedules of 5 Gy × 6F/4F (group A) and 6 Gy × 5 F/4 F/3 F (group B) showing that the incidence of side effects was 55% in Group A and 37% in Group B (26). Hsu et al. compared the dose-fractionation schedules of 7 Gy × 6 F and 8 Gy × 4 F, demonstrating that 8 Gy × 4 F caused fewer side effects than 7 Gy × 6 F (27). Dang et al. found that the incidence of Grades 2–3 rectal side effects was higher in patients who received the regimen with 6–7 fractions than in those who received 3–5 fractions (28). In our study, the incidence of radiation proctitis in Group-5.5 was the same as that in Group-7.0 and higher than that in Group-6.0 (60.00% vs. 46.67%). Moreover, the incidence of radiation proctitis in Group-5.5 was even higher than that in Group-6.0 (60.00% vs. 20.00%), and Group-7.0 (60.00% vs. 33.33%). During each brachytherapy, the positions of the bladder and rectum change to a certain extent, and the dose of brachytherapy drops rapidly, posing challenges in the accurate dose assessment of the OARs. Zhou et al. demonstrated that D_2cc was a predictor of rectal complications (29). Concerning the bladder, Kim et al. found that bladder D_2cc > 95 Gy could induce severe toxicity (30). In our study, the D_2cc value in the rectum was closely related to the incidence of radiation proctitis. However, no correlation was found between the D_2cc value in the bladder and the incidence of radiation cystitis.

If the prescribed dose is excessively high, the EQD₂ based on the linear-quadratic formulation model may be overestimated due to dose saturation and the dynamics competition of chromosomal centromere (31). If the prescribed dose is too low, brachytherapy may be added early in the IMRT stage. Typically, tumor size reduction is not substantial in the early stage of IMRT, making the insertion of applicator a challenging aspect. Additionally, the proximity between the tumors and OARs is relatively short during this phase. On the premise of considering the received dose in OARs, the dose received by HR-CTV is far below the anticipated dose. The prescription dose and the number of fractions directly impact the HR-CTV and OARs dose. In clinical practice, it is crucial to carefully consider these two factors to find a balance, aiming to reduce the dose uncertainty in the target area and minimize the incidence of toxicity and side effects in OARs (e.g., the bladder and rectum).

In this study, no significant differences in the prognosis of the patients or the side effects were observed among our three dose-fractionation schedules. Except for HR-CTV D_90%, HR-CTV D_98%, and rectum D_0.1cc, no significant differences in other dosimetric parameters were observed among the three schedules. The absence of statistical difference between the different groups may be due to the relatively small number of patients. Besides, the median follow-up time was only 30.08 months. Further research with a larger patient cohort and an extended follow-up period is crucial to validate these findings.

The dose-fractionation schedule of 6.0 Gy × 5 fractions provided the most beneficial effects with relatively low OARs doses, suggesting that this dose-fractionation schedule should be prioritized in the clinical application of brachytherapy in cervical cancer.

The datasets presented in this article are not readily available because The raw data supporting the conclusions of this article will be made available by the corresponsding author with reasonable requests. Requests to access the datasets should be directed to 275232962@qq.com.

The studies involving humans were approved by the Ethic Community of Chongqing University Cancer Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. The ethics committee/institutional review board waived the requirement of written informed consent for participation from the participants or the participants’ legal guardians/next of kin because of retrospective nature of the study.

HW: Conceptualization, Formal analysis, Methodology, Writing – original draft, Writing – review & editing. YH: Data curation, Writing – review & editing. DC: Data curation, Writing – review & editing. ML: Data curation, Writing – review & editing. XZ: Conceptualization, Writing – original draft, Supervision, Writing – review & editing.