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Introduction

Cervical cancer remains one of the most prevalent gynecological malignancies among women, ranking fourth globally in terms of both incidence and mortality (1,2). It is the second leading cause of cancer-associated mortalities in women aged 20–39 years (3). Women of lower socioeconomic status experience higher incidence and mortality rates of cervical cancer (4). Moreover, in China, cervical cancer is the second most common malignancy among women after breast cancer (5), with an increasingly younger patient demographic (6), posing notable challenges to their quality of life (QoL) and prognosis.

For patients with early-stage cervical cancer, surgery is the recommended first-line treatment (7). However, in cases of locally advanced cervical cancer, where surgery is not viable, the standard treatment protocol is definitive concurrent chemoradiotherapy (8,9). Whole pelvic radiotherapy serves a pivotal role in treating locally advanced cervical cancer. Commonly utilized techniques include conformal radiation therapy, intensity-modulated radiation therapy (IMRT) and helical tomotherapy (HT) (10,11). Due to the unique anatomical structures in the pelvis, conventional conformal radiotherapy often exposes significant portions of pelvic structures, such as the rectum, intestines, bladder, and femoral heads-to radiation doses approaching or exceeding the prescribed therapeutic levels for the target tumor This frequently results in severe acute and chronic toxicities (12). By contrast, IMRT has demonstrated its capability to reduce doses to organs-at-risk (OARs) and minimize adverse effects to a certain extent (13). However, limitations remain, as certain patients still experience substantial radiation-related toxicities (14). HT, a novel radiotherapy technology, employs unique binary pneumatic multileaf collimators and a 360° rotational beam delivery. It features wide treatment fields, robust modulation capabilities, high conformity in target dose distribution and enhanced protection of normal tissues (15,16). HT achieves precise treatment of tumor targets whilst sparing normal tissues, showcasing notable advantages in several malignancies, particularly head and neck tumors (17,18). Despite these benefits, limited studies have explored the application of HT in whole pelvic radiotherapy for cervical cancer, and evidence supporting its clinical superiority over IMRT remains insufficient.

In locally advanced cervical cancer, the extensive target area and complex anatomical structures present a major challenge in balancing high-dose tumor control with the protection of OARs. Given its technical attributes, HT holds the potential to address this challenge. Therefore, the present study aimed to compare HT and IMRT in terms of dosimetric characteristics, adverse effect profiles and long-term prognostic outcomes in patients with locally advanced cervical cancer. By providing a multidimensional comparison, the present research seeks to offer scientific guidance for optimizing radiotherapy strategies, ultimately improving treatment outcomes and patient QoL.

Materials and methods

General information

The present retrospective study analyzed the clinical data of patients with locally advanced cervical cancer treated at the Cangzhou Integrated Traditional Chinese and Western Medicine Hospital (Cangzhou, China) from January 2015 to December 2023. All patients had histologically- or cytologically-confirmed cervical cancer and received definitive concurrent chemoradiotherapy. The inclusion criteria were as follows: i) Cervical cancer diagnosed through histological or cytological examination; ii) clinical staging of IIB-IVA according to the 2018 revised International Federation of Gynecology and Obstetrics (FIGO) staging system (19,20), as the present study focused on patients with locally advanced cervical cancer for whom concurrent chemoradiotherapy is the standard treatment; iii) definitive concurrent chemoradiotherapy administered as first-line therapy as the uniform treatment protocol; iv) availability of complete and comprehensive imaging data [including computed tomography (CT), magnetic resonance imaging (MRI) or positron emission tomography (PET)/CT] and standardized treatment planning data; and v) signed informed consent permitting the use of patient data for the present study. The exclusion criteria were as follows: i) Concurrent second primary malignancies; ii) organ dysfunction: Severe pulmonary, hepatic, renal or cardiovascular dysfunctions (such as respiratory failure, decompensated cirrhosis, renal failure or recent myocardial infarction); iii) severe gynecological diseases: Conditions such as significant uterine fibroids, uterine polyps or ovarian cysts that interfere with defining the radiation target area; iv) prior therapy received, such as prior radiation therapy or chemotherapy, potentially influencing the study outcomes; v) radiation contraindications, such as inability to tolerate radiotherapy or active infections; vi) incomplete records, such as lacking of essential imaging or treatment planning data; and vii) loss to follow-up, including failure to complete the prescribed treatment or provide sufficient follow-up data.

A total of 112 patients were initially reviewed for eligibility and 12 patients were excluded due to incomplete imaging or treatment planning data, resulting in a final cohort of 100 patients included for analysis. These patients were evenly divided into HT (n=50) and IMRT (n=50) groups. All exclusions were made during the initial data collection phase and no additional patients were removed after that point. Based on available demographic and clinical information, excluded patients did not exhibit systematic differences from those included in the final cohort, and their exclusion is unlikely to have introduced selection bias. Clinical characteristics, including age, body mass index (BMI), Eastern Cooperative Oncology Group (ECOG) score (21), clinical stage, histological type, parametrial invasion, lymph node metastasis, differentiation grade, SCC antigen level, HPV infection status and tumor diameter , were collected for analysis. Treatment allocation was not randomized: In general, patients with more complex disease presentations (such as those with a more advanced clinical stage or extensive lymph node involvement) were more likely to receive HT, owing to its superior dose conformity and ability to spare OARs in complex pelvic irradiation (11). However, treatment selection was not determined by a standardized protocol and may have been influenced by physician preference, equipment availability or other logistical considerations. Notably, baseline imbalances in tumor-related characteristics between the groups were addressed through propensity score matching (PSM), resulting in well-balanced cohorts suitable for comparative outcome analysis.

Treatment methods

All patients underwent standardized pretreatment preparation, including bowel preparation and bladder filling. Bowel preparation: Patients adopted a low-residue diet for ≥3 days prior to treatment, followed by enema administration on the morning of radiotherapy to minimize bowel content interference. Bladder filling: Patients were instructed to drink 800–1,500 ml water 1 h before treatment to ensure optimal bladder filling, facilitating improved dose distribution between targets and OARs.

Patients were positioned supine with arms raised and immobilized using body frames and thermoplastic molds (Ready Medical Srl) to ensure positional reproducibility. Simulation CT scans (Siemens AG) covered the area from the inferior border of the T10 vertebra to the mid-femoral region, with a slice thickness of 3 mm. CT images were transferred via the Digital Imaging and Communication in Medicine protocol to the MONACO system (version 5.1; Elekta Instrument AB) for IMRT design and to the Precision planning system (version 2.0; Accuray Incorporated) for HT planning.

Target delineation adhered to the Radiation Therapy Oncology Group (RTOG) guidelines for cervical cancer (22). A total of two senior radiation oncologists jointly completed and reviewed the delineations. The following target definitions were used: Gross tumor volume, defined as the macroscopic tumor region, including primary lesions and positive lymph nodes, identified via clinical examination and imaging modalities such as CT, MRI or PET; and clinical target volume (CTV), defined as the areas at risk of microscopic disease spread, including the cervix, uterine body, parametrium, upper vaginal segment, pelvic lymphatic drainage regions and para-aortic lymph nodes (PALNs). For positive lymph nodes, the CTV extended 2 cm beyond their boundaries. For patients with radiologically-confirmed metastases in the common iliac and/or PALNs, pelvic field extension and PALN irradiation were implemented in both groups based on identical institutional criteria. In total, 11 patients in the HT group and 9 patients in the IMRT group received PALN irradiation. Target volume delineation and dose prescription for the para-aortic region followed the same protocol in both groups, in accordance with the Chinese Society of Clinical Oncology (CSCO) and National Comprehensive Cancer Network (NCCN) guidelines for cervical cancer radiotherapy (23,24). Planning target volume (PTV) was defined as a 0.5 cm expansion around the CTV to account for positional and motion errors during treatment. OAR definitions included the rectum, small intestine, bladder, pelvic bones, femoral heads and other normal tissues.

Both HT and IMRT plans were created and independently validated for each patient, applying identical dose-volume constraints for targets and OARs (Table I). The IMRT plan was designed using the MONACO system and delivered using the Elekta Synergy accelerator (Elekta Instrument AB). Plans utilized nine evenly distributed coplanar beams optimized iteratively. Prescription doses were PTV 45–50.4 Gy in 25–28 fractions (5 fractions/week), with simultaneous boosts of 10–20 Gy for positive lymph node regions and 5–10 Gy for parametrial or pelvic wall involvement. The HT plan was generated using the Precision planning system and delivered using Radixact® X5 equipment (Accuray Incorporated). Parameters such as field width, pitch and modulation factor were iteratively adjusted to optimize dose distribution. Prescription doses mirrored those of IMRT.

Table I. Dose-volume constraints for targets and organs-at-risk.

Table I.

Dose-volume constraints for targets and organs-at-risk.

Structure	Dose volume constraints
PTV	Minimal dose, 47.5 Gy; Maximal dose, 55 Gy; ≥95% receiving 50 Gy
Bowel	≤35% receiving ≥35 Gy
Bladder	≤50% receiving ≥50 Gy
Rectum	≤50% receiving ≥50 Gy
Pelvic bones	≤50% receiving ≥20 Gy
Femoral head	≤5% receiving ≥50 Gy
Normal tissue	EUD, 18 Gy
Ringa	EUD, 38 Gy

a Dose-shaping structure between PTV + 0.5 cm and PTV + 1.5 cm. PTV, plan target volume; EUD, equivalent uniform dose.

All radiotherapy plans underwent rigorous QA prior to treatment delivery. For both HT and IMRT groups, patient-specific QA was performed by experienced medical physicists using a 3D diode array phantom system (ArcCHECK®; Sun Nuclear Corporation). Verification was performed before the first treatment session for each patient, and dose accuracy was evaluated using gamma index analysis (criteria: 3% dose difference/3 mm distance-to-agreement). A gamma passing rate of ≥95% was required for clinical implementation. In addition, daily image-guided radiotherapy was employed to ensure accurate patient positioning. For IMRT, orthogonal kilovoltage (kV) imaging was used, whilst megavoltage computed tomography was used for HT. These image-guided procedures were performed immediately prior to each treatment session and reviewed by attending radiation oncologists. All QA procedures followed institutional protocols based on recommendations from the American Association of Physicists in Medicine Task Groups 119 and 142 (25,26), ensuring high precision and reproducibility in dose delivery.

Patients received weekly cisplatin (40 mg/m2 per dose) administered via intravenous infusion, for 4–6 consecutive weeks (one cycle per week), concurrent with external beam radiotherapy. For cisplatin-intolerant patients, carboplatin [area under the curve (AUC)=2, weekly] or platinum-based combination regimens were employed. Preventive antiemetics were routinely administered. Combination regimens, whilst recognized in both NCCN and CSCO guidelines as an alternative option for concurrent chemoradiotherapy, are associated with higher toxicity and are less commonly adopted in routine clinical practice for locally advanced cervical cancer. Therefore, in the present study, weekly cisplatin monotherapy was prioritized to reduce treatment-related toxicity and maintain uniformity in systemic therapy across the cohort, thereby minimizing potential confounding in survival outcome analysis.

After 20 external beam therapy sessions, high-dose-rate brachytherapy was integrated. A high dose rate brachytherapy system was used. The target design was as follows: High-risk clinical target volume (HRCTV) was adjusted dynamically based on pelvic MRI before and during treatment. Moreover, the prescription dose was as follows: HRCTV D90 was 30 Gy in 5 fractions (6 Gy per fraction). Combined with external beam therapy, the equivalent total dose (EQD2) for HRCTV D90 was 87–92 Gy.

Dosimetric parameters included PTV coverage, homogeneity index (HI), conformity index (CI) and OAR dose-volume metrics (V5, V10, V20, V30, V40 and V50). The efficacy metrics were based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria (27), and short-term outcomes were categorized as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD), and the objective response rate (ORR) was calculated. Long-term outcomes included 5-year overall survival (OS) and progression-free survival (PFS). The toxicity metrics were acute and chronic radiation-related toxicities, graded per the RTOG criteria (28).

Patients were systematically followed to assess efficacy, prognosis and radiation-related adverse effects. The schedule was as follows: Follow-ups were performed at 1, 3 and 6 months post-radiotherapy, then semi-annually for the first 5 years and annually thereafter. The content of the follow-ups included routine pelvic MRI, chest CT and abdominal ultrasonography, supplemented with PET/CT when necessary. Blood parameters, including squamous cell carcinoma (SCC) antigen, liver and kidney function tests, were monitored. All patients underwent HPV testing as part of the standardized diagnostic protocol. Radiation-related toxicities were assessed using the RTOG criteria. During treatment, toxicities were evaluated weekly by at least one senior attending radiation oncologist (associate chief physician or above), based on clinical examination and patient-reported symptoms, and documented in structured toxicity assessment forms. After treatment completion, toxicities were recorded at each scheduled follow-up visit. All toxicity data used for analysis in the present study were retrospectively extracted from electronic medical records by two independent researchers and cross-verified to ensure consistency. OS was defined as the time from radiotherapy initiation to death from any cause. PFS was defined as the time to disease progression or death. Median follow-up: was 74 months (range, 21–108 months). Among the 100 patients included in the present study, 96 completed the full follow-up protocol. A total of four patients were lost to follow-up after completing initial treatment, and their outcomes were unknown beyond their last documented clinical visit. These patients were included in the Kaplan-Meier survival analyses using right-censoring at the time of their last follow-up.

Data analysis was performed using SPSS 27.0 software (IBM Corp.). Continuous variables were expressed as mean ± standard deviation, and comparisons between groups employed independent t-tests or χ2 tests. Non-parametric data were analyzed using the Mann-Whitney U test. Efficacy and adverse event differences were assessed using χ2 or Fisher's exact tests. Survival analyses were performed using Kaplan-Meier curves, with log-rank tests evaluating group differences. P<0.05 was considered to indicate a statistically significant difference.

A sample size calculation was performed using PASS software (version 15.0; NCSS, LLC) based on a two-sided log-rank test. Assuming a 3-year PFS rate of 70% for the HT group and 50% for the IMRT group (a 20% absolute difference), with α=0.05 and power=0.80, the estimated required sample size was 90 patients (45 in each group). To allow for potential loss to follow-up, 100 patients (50 per group) were recruited, which is sufficient to ensure statistical power for primary outcome comparisons. Although differences in dosimetric parameters were statistically significant and favored HT, PFS was considered as the primary clinical endpoint for power analysis, as it best reflects meaningful therapeutic benefit to patients.

To minimize selection bias, 1:1 PSM was performed using nearest-neighbor matching with a caliper of 0.2. A total of five baseline variables were included in the matching model: Age (≤60 vs. >60 years), ECOG performance status (0 vs. 1), FIGO stage (II vs. III/IV), tumor diameter (≤4 vs. >4 cm) and lymph node metastasis (yes vs. no). After matching, 39 patients were retained in each group (HT and IMRT), with well-balanced baseline characteristics. Following PSM, survival analysis using Kaplan-Meier curves and multivariate Cox proportional hazards regression was performed to further adjust for residual confounding and identify independent prognostic factors for PFS and OS. The multivariate Cox regression model included the following covariates: Age (≤60 vs. >60 years), ECOG performance status (0 vs. 1), tumor diameter (≤4 vs. >4 cm), parametrial invasion (yes vs. no), lymph node metastasis (yes vs. no), differentiation grade (high, moderate and low), FIGO stage (II, III and IV), treatment modality (HT vs. IMRT), HPV status (positive vs. negative) and SCC antigen level (normal vs. elevated, using 1.5 ng/ml as the institutional cutoff). The proportional hazards assumption was verified prior to model fitting.

Results

Clinical characteristics analysis

A total of 100 patients with locally advanced cervical cancer were enrolled in the present study, with 50 patients in each of the HT and IMRT groups. There were no statistically significant differences in baseline characteristics such as age, BMI, ECOG score, tumor stage, histological type, SCC antigen levels or HPV infection status between the two groups (P>0.05), indicating good comparability (Table II).

Table II. Baseline clinical characteristics of the helical tomotherapy and intensity-modulated radiation therapy groups.

Table II.

Baseline clinical characteristics of the helical tomotherapy and intensity-modulated radiation therapy groups.

Characteristic	HT Group (n=50)	IMRT Group (n=50)	χ2	P-value
Age			1.980	0.159
≤60 years	19 (38.0)	26 (52.0)
>60 years	31 (62.0)	24 (48.0)
BMI			2.683	0.261
Normal	24 (48.0)	28 (56.0)
Overweight	15 (30.0)	17 (34.0)
Obese	11 (22.0)	5 (10.0)
ECOG score			1.714	0.190
0	38 (76.0)	32 (64.0)
1	12 (24.0)	18 (36.0)
Tumor diameter (MRI)			0.932	0.334
≤4 cm	13 (26.0)	9 (18.0)
>4 cm	37 (74.0)	41 (82.0)
Parametrial invasion			0.250	0.617
No	9 (18.0)	11 (22.0)
Yes	41 (82.0)	39 (78.0)
Lymph node metastasis			0.386	0.534
No	33 (66.0)	30 (60.0)
Yes	17 (34.0)	20 (40.0)
Histological type				0.912
Squamous cell carcinoma	48 (96.0)	47 (94.0)
Others	2 (4.0)	3 (6.0)
Differentiation grade			1.462	0.481
High	9 (18.0)	14 (28.0)
Moderate	31 (62.0)	28 (56.0)
Low	10 (20.0)	8 (16.0)
Clinical stage (FIGO)			0.915	0.633
Stage II	17 (34.0)	18 (36.0)
Stage III	19 (38.0)	22 (44.0)
Stage IV	14 (28.0)	10 (20.0)
SCC antigen level				0.487
Normal	6 (12.0)	3 (6.0)
Elevated	44 (88.0)	47 (94.0)
HPV infection			2.060	0.151
Negative	16 (32.0)	23 (46.0)
Positive	34 (68.0)	27 (54.0)

[i] Data are presented as n (%). BMI, body mass index; ECOG, Eastern Cooperative Oncology Group; MRI, Magnetic Resonance Imaging; FIGO, International Federation of Gynecology and Obstetrics; SCC, Squamous cell carcinoma; HPV, human papillomavirus.

Target dose distribution

The dosimetric distribution of the target areas in the HT and IMRT groups is presented in Table III. Both groups achieved satisfactory prescription dose coverage of the PTV, but the HT group demonstrated notable advantages in dose homogeneity and conformity. The mean CI in the HT group was 0.94, significantly higher than 0.86 in the IMRT group (t=−3.29; P<0.05). Moreover, the mean HI in the HT group was 1.05, significantly lower than 1.12 in the IMRT group (t=4.98; P<0.05), indicating a more uniform dose distribution in the HT plans. Additionally, the PTV95 values, defined as the percentage of the planning target volume (PTV) receiving at least 95% of the prescribed dose-for the HT and IMRT groups were 99.3 and 99.8%, respectively, with no statistically significant difference between the groups (t=0.25; P=0.62). However, the PTV105 and PTV110 values were significantly lower in the HT group (t=8.36 and t=5.02, respectively; both P<0.05), highlighting the superior control of HT of high-dose regions within the target area. Representative dose distribution images for typical patients are shown in Fig. 1.

Figure 1. Representative dose distribution maps for HT and IMRT plans. Dose distribution maps for the HT plan at different axial, coronal and sagittal slices. (A) Axial dose distribution, showing coverage of the planning target volume and OAR exposure, with color-coded dose gradients indicating high-dose and low-dose regions. (B) Coronal view illustrating dose homogeneity and conformity in the pelvic region. (C) Sagittal representation of dose distribution, highlighting the coverage of the cervical tumor and adjacent structures. Dose distribution maps for the IMRT plan at corresponding axial, coronal and sagittal slices. (D) Axial dose distribution showing the extent of dose conformity and differences in OAR sparing compared with HT. (E) Coronal view depicting the relative dose intensity to pelvic structures. (F) Sagittal section illustrating variations in dose deposition and tumor coverage. HT, helical tomotherapy; IMRT, intensity-modulated radiation therapy; OAR, organ-at-risk.

Table III. Planning target volume dose distribution in helical tomotherapy and intensity-modulated radiation therapy plans.

Table III.

Planning target volume dose distribution in helical tomotherapy and intensity-modulated radiation therapy plans.

Plan	IMRT	HT	t-value	P-value
PTV95, %	99.84±0.03	99.33±0.02	0.25	0.628
PTV100, %	95.75±0.16	95.31±0.24	0.39	0.543
PTV105, %	47.92±9.62	13.57±2.92	8.36	<0.001
PTV110, %	8.28±4.77	0.59±0.26	5.02	<0.001
Dmean, Gy	52.82±0.43	51.43±0.27	6.47	<0.001
CI	0.86±0.04	0.94±0.02	−3.29	<0.001
HI	1.12±0.02	1.05±0.01	4.98	<0.001

[i] Data are presented as mean ± standard deviation. IMRT, intensity-modulated radiation therapy; HT, helical tomotherapy; PTV, plan target volume; CI, conformity index; HI, homogeneity index; D_mean.

Dose distribution to OARs and normal tissues

Significant differences were demonstrated for in the dose distribution to OARs and normal tissues between the HT and IMRT groups (Table IV and Table V). For the rectum, the V30, V40 and V50 values, representing the percentage of rectal volume receiving at least 30, 40, and 50 Gy, respectively, in the HT group were 84.7, 56.2 and 24.1, respectively, with a mean dose of 41.2 Gy compared with the IMRT group (93.2, 64.1 and 28.2%, and 43.4 Gy, respectively; t=3.05; P=0.01), indicating improved rectal protection by HT. For the bladder, the V30, V40 and V50 values in the HT group were 50.6, 28.9 and 13.4%, respectively, with a mean dose of 32.7 Gy compared with the IMRT group (68.8, 38.3 and 17.8%, and 36.4 Gy, respectively; t=6.95; P<0.05), demonstrating the advantage that HT has in bladder protection. The V40 and V50 values were significantly reduced for both femoral heads in the HT group compared with the IMRT group, with mean doses of 14.6 and 16.6% (t=4.92; P<0.001; left) and 13.7 and 15.3% (t=3.83; P<0.05; right), respectively. Moreover, in the HT group, low-to-mid-dose exposure was slightly higher and high-dose exposure (V30, V40 and V50) was slightly lower in the bowel compared with the IMRT group, but the differences in the were not statistically significant (t=0.80; P>0.05). In the pelvic bones, the HT group demonstrated higher exposure in the low-dose regions (V5, V10 and V20; t=−6.00, −6.70 and −2.12, respectively; P<0.05), whilst high-dose region exposure (V30, V40 and V50) was reduced, in comparison with the IMRT group. Finally, in normal tissue, V5, V10 and V20 values were 12.5, 17.5 and 5.2% higher in the HT group, compared with in the IMRT group, with a significantly higher mean dose (20.1 vs. 18.6 Gy; t=−7.31; P<0.001). This reflects the wider low-dose exposure characteristic of the rotational beam delivery of HT.8.

Table IV. Dosimetric distribution of organs-at-risk in helical tomotherapy and intensity-modulated radiation therapy plans.

Table IV.

Dosimetric distribution of organs-at-risk in helical tomotherapy and intensity-modulated radiation therapy plans.

A, Bowel
Plan	IMRT	HT	t-value	P-value
V5, %	93.2±5.1	96.3±1.2	−1.09	0.264
V10, %	85.2±6.4	88.3±7.2	−1.32	0.198
V20, %	63.2±6.1	64.3±8.2	−0.33	0.742
V30, %	38.7±6.3	32.6±9.1	2.69	0.039
V40, %	21.2±2.3	17.4±6.2	1.67	0.133
V50, %	8.8±2.1	8.0±3.8	0.92	0.384
Dmean, Gy	26.7±6.0	26.2±7.1	0.80	0.455
B, Rectum
Plan	IMRT	HT	t-value	P-value
V5, %	99.2±0.5	100.0±0.0	−1.17	0.271
V10, %	98.2±1.1	100.0±0.0	−1.62	0.145
V20, %	96.8±2.6	97.4±1.2	−1.30	0.246
V30, %	93.2±5.3	84.7±8.1	3.32	<0.001
V40, %	64.1±12.2	56.2±7.4	3.07	0.017
V50, %	28.2±10.2	24.1±5.6	2.39	0.045
Dmean, Gy	43.4±6.5	41.2±5.3	3.05	0.014
C, Bladder
Plan	IMRT	HT	t-value	P-value
V5, %	100.0±0.0	100.0±0.0	–	–
V10, %	99.3±0.6	100.0±0.0	−1.73	0.112
V20, %	89.2±2.5	86.1±4.2	0.86	0.421
V30, %	68.8±5.4	50.6±6.7	4.92	<0.001
V40, %	38.3±15.1	28.9±7.4	5.77	<0.001
V50, %	17.8±8.5	13.4±3.4	4.65	<0.001
Dmean, Gy	36.4±5.2	32.7±6.6	6.95	<0.001
D, Pelvic bones
Plan	IMRT	HT	t-value	P-value
V5, %	92.2±4.7	97.4±2.7	−6.00	<0.001
V10, %	85.6±7.4	92.3±3.3	−6.70	<0.001
V20, %	65.4±9.1	68.3±4.5	−2.12	0.079
V30, %	45.6±5.8	43.4±2.1	1.41	0.197
V40, %	24.7±4.1	23.6±2.8	0.43	0.682
V50, %	9.4±5.5	9.1±2.2	1.63	0.146
Dmean, Gy	27.5±1.3	28.2±0.7	−1.44	0.264
E, Left femoral head
Plan	IMRT	HT	t-value	P-value
V5, %	100.0±0.0	100.0±0.0	–	–
V10, %	99.7±0.3	100.0±0.0	−0.39	0.763
V20, %	88.6±7.5	86.7±5.4	0.92	0.453
V30, %	67.9±2.7	66.4±1.8	0.85	0.467
V40, %	9.2±2.0	7.8±1.9	2.55	0.048
V50, %	0.37±1.4	0.16±2.1	3.61	<0.001
Dmean, Gy	16.6±4.0	14.6±3.4	4.92	<0.001
F, Right femoral head
Plan	IMRT	HT	t-value	P-value
V5, %	99.6±0.4	100.0±0.0	−0.16	0.899
V10, %	98.3±1.1	99.7±0.6	−0.32	0.741
V20, %	90.2±3.2	87.7±6.4	1.06	0.268
V30, %	67.0±2.1	66.8±1.0	0.45	0.685
V40, %	13.4±0.1	12.2±1.5	1.84	0.057
V50, %	0.92±3.4	0.48±1.0	2.91	0.023
Dmean, Gy	15.3±4.5	13.7±2.8	3.83	<0.001

[i] Data are presented as mean ± standard deviation. IMRT, intensity-modulated radiation therapy; HT, helical tomotherapy; PTV, planning target volume.

Table V. Dosimetric distribution of normal tissues in helical tomotherapy and intensity-modulated radiation therapy plans.

Table V.

Dosimetric distribution of normal tissues in helical tomotherapy and intensity-modulated radiation therapy plans.

Plan	IMRT	HT	t-value	P-value
V5, %	79.7±4.3	92.2±2.4	−8.25	<0.001
V10, %	63.4±5.7	80.9±3.8	−9.13	<0.001
V20, %	37.3±4.6	42.5±4.2	−4.92	<0.001
V30, %	18.5±4.4	17.6±2.7	0.99	0.335
V40, %	7.2±1.4	6.3±2.2	0.56	0.667
V50, %	1.3±0.1	1.0±0.2	0.69	0.516
Dmean, Gy	18.6±3.9	20.1±5.1	−7.31	<0.001

[i] Data are presented as mean ± standard deviation. IMRT, intensity-modulated radiation therapy; HT, helical tomotherapy; PTV, planning target volume.

Comparison of OS and PFS

The median OS and PFS for all patients were 73.9 and 61.2 months, respectively (Fig. 2). Furthermore, the median OS was 75.8 months in the HT group and 72.4 months in the IMRT group, with 5-year OS rates of 72.0 and 68.0%, respectively. There was no statistically significant difference between the groups [hazard ratio (HR), 0.756; 95% confidence interval (CI), 0.486–1.175; χ2=1.570; P=0.210; Fig. 3A]. The median PFS was 67.2 months in the HT group, significantly longer than 60.3 months in the IMRT group. The 5-year PFS rates were 60.0 and 52.0%, respectively (HR, 0.612; 95% CI, 0.386–0.971; χ2=4.539; P=0.033; Fig. 3B). Recurrence pattern analysis revealed that the overall recurrence rate was lower in the HT group (25/50; 50.0%) compared with in the IMRT group (34/50; 68.0%); however, the difference was not statistically significant (χ2=3.348; P=0.067). Specifically, local recurrence occurred in 3 patients (6.0%) in the HT group and 6 patients (12.0%) in the IMRT group; and regional recurrence was observed in 8 patients (16.0%) in the HT group and 13 patients (26.0%) in the IMRT group. Moreover, distant metastases occurred in 14 patients (28.0%) in the HT group and 15 patients (30.0%) in the IMRT group. Although none of the individual recurrence patterns reached statistical significance, the overall trend suggests a potential benefit of HT in reducing local and regional recurrence, potentially contributing to the observed improvement in PFS.

Figure 2. Kaplan-Meier survival curves for all patients. (A) OS. (B) PFS. OS, overall survival; PFS, progression-free survival.

Figure 3. Kaplan-Meier curves comparing OS and PFS between the HT and IMRT groups. (A) OS comparison. (B) PFS comparison. HT, helical tomotherapy; IMRT, intensity-modulated radiation therapy; OS, overall survival; PFS, progression-free survival.

Local tumor control

The 5-year local control rate (LCR) was 82.0% in the HT group and 66.0% in the IMRT group. Moreover, the median local control duration was 69.2 months (95% CI, 24.7–86.7) in the HT group and 62.6 months (95% CI, 15.7–84.9) in the IMRT group. Kaplan-Meier analysis demonstrated a statistically significant improvement in LCR in the HT group compared with in the IMRT group (HR, 0.529; 95% CI, 0.339–0.826; χ2=8.246; P=0.004; Fig. 4).

Figure 4. Kaplan-Meier curves comparing LCR between the HT and IMRT groups. HT, helical tomotherapy; IMRT, intensity-modulated radiation therapy; LCR, local control rate.

Treatment efficacy

According to RECIST 1.1 criteria, the HT group achieved a CR rate of 64.0% (32/50), PR rate of 28.0% (14/50) and SD rate of 8.0% (4/50), with no PD cases. The ORR was 92.0%. In the IMRT group, CR, PR, SD and PD rates were 54.0% (27/50), 32.0% (16/50), 12.0% (6/50) and 2.0% (1/50), respectively, with an ORR of 86.0%. There was no significant difference in ORR between the two groups (χ2=0.919; P=0.338; Fig. 5).

Figure 5. Treatment efficacy in the HT and IMRT groups. (A) Efficacy outcomes in the HT group. (B) Efficacy outcomes in the IMRT group. HT, helical tomotherapy; IMRT, intensity-modulated radiation therapy; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.

Radiation-related toxicity

Radiation-related adverse events were reported in both groups, with differences summarized in Table VI. Grade 1–2 toxicity occurred in 68.0% (34/50) of HT patients compared with 84.0% (42/50) of IMRT patients. Grade 3 toxicity occurred in 8.0% (4/50) of HT patients compared with 12.0% (6/50) of IMRT patients, with no significant difference (χ2=0.444; P=0.505). However, HT exhibited superior dosimetric protection for the rectum and bladder (Table IV), though the incidence of severe adverse events (Grade ≥3) was comparable between the two groups (Table VI).

Table VI. Comparison of radiotherapy-related toxicities in helical tomotherapy and intensity-modulated radiation therapy groups.

Table VI.

Comparison of radiotherapy-related toxicities in helical tomotherapy and intensity-modulated radiation therapy groups.

Toxicity type	HT group (n=50)	IMRT group (n=50)	P-value
Radiation enteritis			0.319
Grade 1–2	17 (34.0)	24 (48.0)
Grade ≥3	1 (2.0)	2 (4.0)
Radiation cystitis			0.109
Grade 1–2	19 (38.0)	27 (54.0)
Grade ≥3	0 (0.0)	1 (2.0)
Radiation vaginitis			0.087
Grade 1–2	15 (30.0)	32 (64.0)
Grade ≥3	0 (0.0)	0 (0.0)
Radiation dermatitis			0.682
Grade 1–2	21 (42.0)	18 (36.0)
Grade ≥3	0 (0.0)	0 (0.0)
Bone marrow suppression			0.057
Grade 1–2	26 (52.0)	37 (74.0)
Grade ≥3	3 (6.0)	3 (6.0)

[i] Data are presented as n (%). IMRT, intensity-modulated radiation therapy; HT, helical tomotherapy.

Treatment compliance and chemotherapy tolerance

Of the 100 patients, 87 (87.0%) received the institutional standard regimen of weekly cisplatin (40 mg/m2). Among them, 76 patients (87.4%) completed the full course of 5–6 cycles without modification. The remaining 11 patients (12.6%) experienced notable toxicity, including gastrointestinal side effects (n=3) and hematologic toxicity (n=8), necessitating dose reductions or treatment delays. A total of 13 patients (13.0%) were deemed unsuitable for cisplatin due to baseline renal impairment or severe gastrointestinal intolerance and were switched to weekly carboplatin (AUC=2) as an alternative regimen. No patients received combined chemotherapy regimens such as cisplatin plus paclitaxel. All patients successfully completed the planned radiotherapy regimen, including both external beam radiation and brachytherapy, without any dose reductions. However, 4 patients (4.0%) required minor adaptive planning during treatment due to anatomical changes such as variations in bladder filling or weight loss. These adaptations did not affect the prescribed dose and were implemented under image-guided verification with a weekly plan review.

Post-PSM analysis of baseline characteristics, survival outcomes and toxicities

After performing 1:1 PSM with a caliper of 0.2, 39 matched pairs from the HT and IMRT groups were included in the final analysis. The baseline characteristics, including age, ECOG performance status, FIGO stage, tumor diameter and lymph node metastasis, were well-balanced between the two groups following matching. Detailed comparisons of these characteristics are presented in Table VII, with no significant differences observed (all P>0.05). Moreover, Kaplan-Meier survival curves demonstrated no significant difference in OS between the two groups (χ2=0.249; P=0.618; Fig. 6); however, there was a significantly improved PFS rate in the HT group compared with in the IMRT group (χ2=5.737; P=0.017; Fig. 7).

Figure 6. Kaplan-Meier curves comparing OS between the HT and IMRT groups after propensity score matching. OS, overall survival; HT, helical tomotherapy; IMRT, intensity-modulated radiation therapy.

Figure 7. Kaplan-Meier curves comparing PFS between the HT and IMRT groups after propensity score matching. PFS, progression-free survival; HT, helical tomotherapy; IMRT, intensity-modulated radiation therapy.

Table VII. Comparison of baseline characteristics between helical tomotherapy and intensity-modulated radiation therapy groups after propensity score matching.

Table VII.

Comparison of baseline characteristics between helical tomotherapy and intensity-modulated radiation therapy groups after propensity score matching.

Characteristic	HT group (n=39)	IMRT group (n=39)	χ2	P-value
Age			0.473	0.492
≤60 years	15 (38.5)	18 (46.2)
>60 years	24 (61.5)	21 (53.8)
ECOG score			1.258	0.262
0	33 (84.6)	29 (74.4)
1	6 (15.4)	10 (25.6)
Tumor diameter (MRI)			0.831	0.362
≤4 cm	8 (20.5)	5 (12.8)
>4 cm	31 (79.5)	34 (87.2)
Lymph node metastasis			0.867	0.352
No	26 (66.7)	22 (56.4)
Yes	13 (33.3)	17 (43.6)
Clinical stage (FIGO)			0.748	0.688
Stage II	13 (33.3)	14 (35.9)
Stage III	17 (43.6)	19 (48.7)
Stage IV	9 (23.1)	6 (15.4)

[i] Data are presented as n (%). IMRT, intensity-modulated radiation therapy; HT, helical tomotherapy; ECOG, Eastern Cooperative Oncology Group; MRI, magnetic resonance imaging; FIGO, International Federation of Gynecology and Obstetrics.

Multivariate Cox regression analysis revealed that, for OS, FIGO stage (HR, 6.024; 95% CI, 1.961–10.258; P<0.001) and lymph node metastasis (HR, 1.703; 95% CI, 1.080–2.673; P=0.039) were significant independent prognostic factors, whilst treatment modality revealed a nonsignificant trend (HR, 1.517; 95% CI, 0.784–2.361; P=0.089) (Table VIII). Moreover, SCC antigen level (HR, 1.327; 95% CI, 0.758–3.015; P=0.194) and HPV status (HR, 1.269; 95% CI, 0.692–2.438; P=0.461) were not significantly associated with OS (Table VIII). Multivariate Cox regression analysis also revealed that treatment modality (HT vs. IMRT) was an independent predictor for PFS (HR, 2.193; 95% CI, 1.188–4.049; P=0.012) (Table IX). In addition, FIGO stage (P<0.001) and lymph node metastasis P=0.027) were significant predictors of PFS. However, SCC antigen level (HR, 1.203; 95% CI, 0.759–2.681; P=0.614) and HPV status (HR, 1.182; 95% CI, 0.527–2.284) were not significantly associated with PFS, although both were retained in the model for completeness (Table IX).

Table VIII. Univariate and multivariate Cox regression analysis for overall survival after propensity score matching.

Table VIII.

Univariate and multivariate Cox regression analysis for overall survival after propensity score matching.

	Univariate analysis			Multivariate analysis
Characteristic	HR	95% CI	P-value	HR	95% CI	P-value
Age
≤60 years	1.000
>60 years	1.059	0.578–1.601	0.802
ECOG score
0	1.000
1	1.271	0.847–1.986	0.457
Tumor diameter (MRI)
≤4 cm	1.000
>4 cm	1.216	0.686–1.914	0.502
Parametrial invasion
No	1.000
Yes	1.393	0.864–2.209	0.162
Lymph node metastasis
No	1.000			1.000
Yes	1.826	1.138–2.812	0.021	1.703	1.080–2.673	0.039
Differentiation grade
High	1.000
Moderate	1.086	0.653–1.852	0.758
Low	1.404	0.817–2.328	0.152
Clinical stage (FIGO)
Stage II	1.000		<0.001	1.000		<0.001
Stage III	4.139	1.364–8.927	<0.001	4.627	1.627–9.364	<0.001
Stage IV	5.657	1.620–9.534	<0.001	6.024	1.961–10.258	<0.001
Treatment modality
HT	1.000			1.000
IMRT	1.662	0.988–2.567	0.048	1.517	0.784–2.361	0.089
HPV status
Negative	1.000
Positive	1.269	0.692–2.438	0.461
SCC antigen level
Normal	1.000
Elevated	1.327	0.758–3.015	0.194

[i] HR, hazard ratio; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; MRI, magnetic resonance imaging; FIGO, International Federation of Gynecology and Obstetrics; IMRT, intensity-modulated radiation therapy; HT, helical tomotherapy; HPV, human papillomavirus; SCC, squamous cell carcinoma.

Table IX. Univariate and multivariate Cox regression analysis for progression-free survival after propensity score matching.

Table IX.

Univariate and multivariate Cox regression analysis for progression-free survival after propensity score matching.

	Univariate analysis			Multivariate analysis
Characteristic	HR	95% CI	P-value	HR	95% CI	P-value
Age
≤60 years	1.000
>60 years	1.245	0.645–2.523	0.510
ECOG score
0	1.000
1	1.397	0.785–2.387	0.259
Tumor diameter (MRI)
≤4 cm	1.000			1.000
>4 cm	1.935	0.937–3.262	0.044	1.623	0.752–2.967	0.115
Parametrial invasion
No	1.000
Yes	1.426	0.628–3.024	0.212
Lymph node metastasis
No	1.000			1.000
Yes	2.373	0.927–4.285	0.008	1.984	0.751–4.128	0.027
Differentiation grade
High	1.000
Moderate	1.009	0.536–2.614	0.967
Low	1.158	0.546–2.935	0.852
Clinical stage (FIGO)
Stage II	1.000		<0.001	1.000		<0.001
Stage III	2.849	0.945–5.694	<0.001	4.213	1.568–8.657	<0.001
Stage IV	3.591	1.317–7.658	<0.001	5.683	2.301–9.657	<0.001
Treatment modality
HT	1.000			1.000
IMRT	2.692	0.859–4.627	<0.001	2.193	0.932–5.128	0.012
HPV status
Negative	1.000
Positive	1.182	0.527–2.284	0.793
SCC antigen level
Normal	1.000
Elevated	1.203	0.759–2.681	0.614

[i] HR, hazard ratio; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; MRI, magnetic resonance imaging; FIGO, International Federation of Gynecology and Obstetrics; IMRT, intensity-modulated radiation therapy; HT, helical tomotherapy; HPV, human papillomavirus; SCC, squamous cell carcinoma.

Additionally, treatment-related toxicities were compared between the HT and IMRT groups after PSM (Table X). Although no statistically significant differences were demonstrated, the HT group exhibited a lower incidence of grade 1–2 gastrointestinal, hematological and vaginal toxicities compared with that of the IMRT group. Moreover, no significant differences in grade ≥3 toxicities were observed between the two groups.

Table X. Comparison of radiotherapy-related toxicities between helical tomotherapy and intensity-modulated radiation therapy groups after propensity score matching.

Table X.

Comparison of radiotherapy-related toxicities between helical tomotherapy and intensity-modulated radiation therapy groups after propensity score matching.

Toxicity type	HT group (n=39)	IMRT group (n=39)	P-value
Radiation enteritis			0.208
Grade 1–2	14 (35.9)	21 (53.8)
Grade ≥3	1 (2.6)	1 (2.6)
Radiation cystitis			0.109
Grade 1–2	18 (46.2)	25 (64.1)
Grade ≥3	0 (0.0)	1 (2.6)
Radiation vaginitis			0.057
Grade 1–2	13 (33.3)	29 (74.4)
Grade ≥3	0 (0.0)	0 (0.0)
Radiation dermatitis			0.647
Grade 1–2	18 (46.2)	15 (38.5)
Grade ≥3	0 (0.0)	0 (0.0)
Bone marrow suppression			0.068
Grade 1–2	24 (61.5)	35 (89.7)
Grade ≥3	2 (2.6)	3 (7.7)

[i] Data are presented as n (%). HT, helical tomotherapy; IMRT, intensity-modulated radiation therapy.

Discussion

With the widespread implementation and continuous refinement of HT, its advantages in target dose homogeneity, conformity and protection of OARs have been assessed in the treatment of several malignancies, including head and neck cancers, intracranial tumors and prostate cancer (29,30). Sheng et al (31) reported that, compared with fixed gantry angle IMRT, HT improved dose conformity and homogeneity whilst providing superior protection for critical structures such as the parotid glands in nasopharyngeal carcinoma. Lee et al (32) arrived at similar conclusions. However, the unique characteristics of whole pelvic radiotherapy for cervical cancer (including target and OAR geometry, dose-volume prescriptions and OAR tolerances) make it distinct from other malignancies (33). Limited studies have addressed the dosimetric characteristics of HT in this context (34–36). The present study systematically compared HT and IMRT in the treatment of locally advanced cervical cancer. It analyzed dosimetric distributions in targets and OARs, as well as clinical outcomes and adverse event profiles, to provide quantitative data for improving treatment planning and assessing the potential clinical advantages of HT.

The results of the present study demonstrated that HT outperformed IMRT in terms of target dose conformity and homogeneity, as shown by a higher CI and a lower HI. These findings indicate that HT delivers more precise target coverage whilst reducing excessive high-dose regions within the target. These improvements stem from the 360° rotational delivery of HT, which enables highly uniform dose distribution (37). Optimizing target dose distribution not only enhances tumor control but also mitigates potential risks of normal tissue damage from dose hotspots (38). HT demonstrated significant advantages in reducing high-dose exposure (V40 and V50) to critical structures such as the rectum, bladder and femoral heads, with corresponding reductions in mean dose. High-dose protection of OARs is crucial for minimizing both acute and late radiation injuries (39). These results suggest that HT may have a potential clinical advantage in reducing radiation-induced toxicities, particularly in the rectum and bladder. However, due to its rotational beam delivery, HT exhibited greater exposure of normal tissues to low-dose radiation (V5, V10 and V20), which may increase long-term risks such as bone marrow suppression, fractures and secondary malignancies (40,41). This warrants particular attention in younger patients.

In the present study, HT demonstrated a significant improvement in PFS, with a median PFS of 67.2 compared with 60.3 months for IMRT (χ2=4.539; P=0.033). However, there was no statistically significant difference in OS between the two groups. In addition to prolonged PFS, the HT group also demonstrated a significantly higher 5-year LCR (82.0 vs. 66.0%) and longer median local control duration (69.2 vs. 62.6 months). These results indicate that the dosimetric advantages of HT (specifically, improved conformity and homogeneity of dose distribution) may translate into more effective local tumor control. This is supported by the recurrence pattern analysis, which revealed a lower overall recurrence rate in the HT group (50.0 vs. 68.0%) and fewer local and regional relapses. Although individual recurrence types did not reach statistical significance, the overall trend suggests that HT may provide greater locoregional control, which likely contributed to the observed improvement in PFS.

Given the critical role of adequate dose coverage and hotspot avoidance in pelvic radiotherapy (42), this finding further supports the clinical relevance of optimizing radiotherapy techniques beyond traditional endpoints such as toxicity or PFS. Moreover, whilst this analysis was based on the full cohort before PSM, the magnitude of difference in local control suggests a true therapeutic gain attributable to the physical precision of HT. The 5-year OS rates for HT and IMRT were 72.0 and 68.0%, respectively. The higher ORR observed in the HT group (92.0 vs. 86.0%) further highlights its potential clinical benefits. Furthermore, the improvement in PFS observed with HT likely reflects its superior local control and reduced treatment-related toxicity. By contrast, OS can be influenced by a wider range of factors beyond initial local treatment efficacy, including patterns of distant metastasis, salvage therapies, comorbidities and post-progression care (43). The relatively small sample size and limited number of survival events may also reduce the statistical power to detect OS differences.

PFS may serve as a more sensitive and immediate endpoint for evaluating the clinical benefits of advanced radiotherapy techniques such as HT, particularly in retrospective cohort studies with long follow-up durations. Given the clinical relevance of PFS in reflecting disease control, and its statistically significant difference observed in the present study, PFS was selected as the primary endpoint for power and sample size estimation. Whilst dosimetric parameters, such as CI and V40, provide technical insight into treatment planning quality, they do not directly translate to patient outcomes. The observed improvement in PFS with HT likely reflects enhanced short-term local tumor control due to superior dose conformity and reduced toxicity.

However, OS is multifactorial and heavily influenced by systemic therapies, including concurrent chemotherapy, salvage treatments and control of distant micrometastases (44). Although all patients received concurrent platinum-based chemoradiotherapy in the present study, variations in disease biology, treatment response and post-progression management may have contributed to the lack of a significant OS difference. This highlights the complementary role of systemic therapy in determining long-term survival outcomes. Therefore, sample size justification was based on expected differences in PFS, which improves the representation of the clinically meaningful therapeutic benefit (45). The findings of the present study align with those of Li et al (45), who reported comparable ORR rates between HT and IMRT but no significant differences in 1- or 3-year OS and PFS rates. The extended follow-up in the present study (median, 74 months) may explain the observed improvement in long-term PFS with HT, suggesting that HT could provide incremental benefits in the long-term management of locally advanced cervical cancer. To reduce the potential impact of selection bias inherent in retrospective studies, PSM was performed based on clinically relevant baseline characteristics. After matching, the two treatment groups were well balanced in terms of age, ECOG score, FIGO stage, tumor diameter and lymph node status. Notably, survival analyses in the matched cohort yielded consistent results, with HT still demonstrating a significant improvement in PFS. Furthermore, multivariate Cox regression confirmed that treatment modality remained an independent predictor of PFS, along with FIGO stage and lymph node metastasis. These findings enhance the robustness of the results of the present study and support the potential clinical value of HT in improving disease control. HPV status and SCC antigen levels were also included in the multivariate analysis, given their established relevance in cervical cancer prognosis. However, neither variable was revealed to be significantly associated with OS or PFS in the cohort. This may reflect limited statistical power or lack of subtype stratification, but their inclusion strengthens the transparency and completeness of the prognostic model. However, larger, multi-center studies with longer follow-up durations are necessary to validate these findings. Reducing the irradiated volume of critical OARs, such as the rectum and bladder, is essential for mitigating both acute and chronic radiation injuries.

In the present study, the HT group exhibited lower incidences of Grade 1–2 radiation-related toxicities, particularly for rectal and bladder toxicity. However, there were no significant differences in the incidence of severe (Grade ≥3) toxicities between the two groups, possibly due to the limited sample size. The wider low-dose radiation exposure associated with HT, resulting from its rotational delivery pattern, warrants further optimization in treatment planning. Whilst no significant increase in acute gastrointestinal toxicity was observed in the present study, the extended low-dose exposure to intestinal tissues in the HT group raises potential concerns regarding late radiation enteritis. Chronic gastrointestinal complications, such as radiation-induced enteritis, can develop months or even years after treatment, causing long-term bowel dysfunction, diarrhea and malabsorption, which notably impair patient QoL. The broader low-dose exposure pattern in HT, which affects the small and large intestines, increases the risk of such complications over time (46). Although the present study did not assess these late effects comprehensively, the risk of delayed gastrointestinal toxicities, including bowel stenosis, chronic diarrhea and enteritis, should be considered when evaluating the long-term safety of HT. These complications, whilst not immediately life-threatening, can have a profound impact on patient well-being and functional status. Given the potential for delayed gastrointestinal toxicities due to low-dose radiation exposure, it is crucial that future studies incorporate structured assessments of long-term gastrointestinal sequelae, particularly when evaluating radiotherapy modalities with broader low-dose distribution patterns such as HT. Implementing advanced dose-volume constraints, such as those that specifically limit low-dose exposure to critical gastrointestinal tissues, will be essential to minimize these risks. Moreover, long-term monitoring of gastrointestinal function, including the use of validated instruments for QoL assessment, will help to evaluate the true patient-centered benefits of HT. Further investigation into the incidence of radiation enteritis, chronic bowel dysfunction and other late effects in a larger cohort with longer follow-up is urgently needed to fully understand the biological consequences of low-dose radiation exposure in HT.

Moreover, although the differences in grade ≥3 toxicities between HT and IMRT groups were not statistically significant, the HT group exhibited lower rates of mild-to-moderate gastrointestinal, hematologic and vaginal toxicities. These findings, whilst not definitive, suggest a trend toward improved tolerability with HT, which may be clinically meaningful, particularly in younger patients or those with borderline treatment tolerance. Furthermore, although Grade 1–2 toxicities are generally considered clinically manageable, they may still have meaningful effects on patient comfort, psychological well-being and overall QoL, especially when symptoms are persistent (47). Previous studies have indicated that mild genitourinary and gastrointestinal toxicities, even when not classified as severe, can markedly impair daily functioning and patient-reported outcomes. Lapierre et al (48) emphasized the importance of reducing late toxicity to improve QoL following radiotherapy. Similarly, the RAPIDO trial reported that lower-grade symptoms, such as mild diarrhea or urinary irritation, were associated with reductions in QoL scores in pelvic radiotherapy patients (49). Although the present study did not incorporate a formal QoL instrument, the reduced incidence of low-grade toxicities in the HT group may suggest a potential patient-centered benefit that warrants further investigation in future prospective studies using validated QoL scales.

Although HT significantly reduces high-dose exposure to critical structures, its rotational delivery pattern leads to broader low-dose radiation exposure (V5-V20) in normal tissues, including the pelvic bone marrow and soft tissues. This raises concerns about potential long-term effects such as chronic bone marrow suppression, secondary malignancies or radiation-induced fibrosis. In the present study, no secondary cancers or significant differences in late toxicities were observed during the median 74-month follow-up. However, the relatively small cohort and limited event rate preclude definitive conclusions. Future prospective studies with longer follow-up are needed to evaluate the biological consequences of low-dose radiation exposure in HT. Additionally, PALN irradiation was selectively applied to patients with confirmed metastases in the common iliac or para-aortic regions, in accordance with institutional criteria and CSCO/NCCN guidelines. The number of patients receiving PALN irradiation was similar between groups (HT, n=11; IMRT, n=9), and the delineation protocols and dose prescriptions were standardized. Therefore, differences in PALN coverage are unlikely to have influenced the comparative efficacy outcomes between radiotherapy techniques.

The present study is among the first to systematically compare HT and IMRT in the treatment of locally advanced cervical cancer, to the best of our knowledge. By assessing target dose uniformity, conformity and OAR protection, it provides comprehensive insights into the dosimetric advantages of HT. By incorporating PSM and multivariate regression analysis, the present study also strengthens the validity of the clinical outcome comparisons between the two modalities. Additionally, with a median follow-up of 74 months, the present study evaluated the potential value of HT in improving both short-term and long-term outcomes. However, several limitations must be acknowledged: i) The single-center study may have limitations in terms of generalizability. However, treatment protocols, radiotherapy equipment and diagnostic workflows in the Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine are largely consistent with national and international standards, which enhances the comparability and potential generalizability of the findings; ii) The relatively small sample size and limited follow-up may affect the assessment of rare events, such as severe adverse reactions or long-term outcomes; iii) Variations in parameter optimization between HT and IMRT plans may have influenced the results; iv) The study exclusively included patients with FIGO stages IIB-IVA, consistent with the standard definition of locally advanced cervical cancer. As early-stage patients (FIGO I) are typically treated surgically rather than with chemoradiotherapy, the findings may not be generalizable to this population; v) the present study did not perform subgroup analyses by FIGO stage (such as Stage II vs. III/IV) due to the limited number of patients within each subgroup. As a result, potential stage-specific differences in the efficacy of HT could not be evaluated. Future prospective studies with larger cohorts should perform FIGO stage-specific subgroup analyses to determine whether the clinical benefits of HT are consistent across different tumor stages; vi) Although the median follow-up duration in the present study was relatively long (74 months), data on specific late complications such as rectal stenosis, bladder fibrosis or sexual dysfunction were not systematically collected and thus could not be analyzed. The present study did not specifically include follow-up assessments of pelvic bone mineral density, femoral head necrosis or fractures. However, during the median follow-up period of 74 months, no cases of clinically reported pelvic fractures or femoral head necrosis were documented in either group. However, the increased low- to mid-dose exposure to pelvic bones observed with HT indicates that long-term bone toxicity is an important consideration. Future studies incorporating imaging-based bone density evaluations and musculoskeletal toxicity monitoring will be valuable in improving the characterization of these risks. These complications are clinically important in pelvic radiotherapy, particularly for patients with long-term survival. Future prospective studies should incorporate structured long-term toxicity assessments, including functional outcomes and QoL domains, to comprehensively evaluate the impact of advanced radiotherapy techniques. Furthermore, the present study did not include formal patient-reported QoL assessments, such as the EORTC QLQ-CX24 or FACT-Cx (50,51). Whilst prior studies have reported that reduced toxicity may translate into improved QoL (52–54), the absence of direct patient-reported outcomes limited the ability of the present study to confirm this association in the study cohort. Future prospective studies should integrate validated QoL instruments to comprehensively evaluate the symptomatic and functional impact of advanced radiotherapy techniques such as HT. Future research should also focus on multi-center, large-scale and prospective randomized controlled trials to further validate the clinical advantages of HT. Prolonged follow-up is necessary to assess long-term toxicity and efficacy comprehensively. Furthermore, advancements in artificial intelligence (AI)-assisted treatment planning hold promise for improving dose distribution whilst minimizing normal tissue exposure, enabling more personalized and effective radiotherapy.

In conclusion, the present study compared the dosimetric distribution, clinical efficacy and radiation-related toxicity of HT and IMRT in the treatment of locally advanced cervical cancer. HT demonstrated significant advantages in target dose homogeneity, conformity and protection of high-dose regions in OARs. It also revealed potential benefits in improving PFS and ORR. However, the increased exposure of normal tissues to low-dose radiation with HT remains a limitation, necessitating further optimization and investigation.

As an advanced radiotherapy technology, HT provides a promising option for personalized treatment of locally advanced cervical cancer. Future studies incorporating optimized HT planning and long-term, multi-center clinical research will help realize its full potential in enhancing patient survival outcomes and minimizing radiation toxicity. In addition, AI-assisted treatment planning, particularly using deep learning and knowledge-based optimization algorithms, has shown potential to enhance the efficiency and consistency of HT planning. By integrating large-scale clinical data and patient-specific anatomy, AI-based systems may further reduce OAR dose exposure, improve plan quality and support individualized radiotherapy strategies. Although not applied in the present study, such technologies represent a promising direction for future clinical implementation and research. Despite the potential clinical advantages of HT, it requires specialized equipment, infrastructure and expertise, which may limit its availability in low- and middle-income settings. The present study did not include a formal cost-effectiveness analysis. However, the long-term reduction in toxicity and improvement in disease control associated with HT may contribute to downstream cost savings. Comprehensive health economic evaluations, including direct and indirect costs, are warranted in future research to assess the feasibility and sustainability of HT in different clinical and resource contexts. Finally, a multicenter prospective trial is warranted to generate high-level evidence confirming the therapeutic benefits of HT and to evaluate its generalizability across different clinical environments. Such efforts may also facilitate the standardization of HT protocols, promote cost-benefit analysis and support more widespread clinical adoption in both high- and low-resource settings.

Acknowledgements

Not applicable.

Funding

The present study was supported by the Self-funded Project under the Key Research and Development Program of Cangzhou City (Project Number: 222106021).

Availability of data and materials

The data generated in the present study may be requested from the corresponding author.

Authors' contributions

TX performed the data analysis and paper writing. YS was responsible for the research design and guided the revision of the paper. JZ designed the study and analyzed data. BW and LX interpreted data. TX and YS confirm the authenticity of all the raw data. All authors read and approved the final manuscript.

Ethics approval and consent to participate

The current study was performed in accordance with the Declaration of Helsinki and approved by the local ethics committee of the Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine-Hebei Province (Cangzhou, China; approval no. CZX2023062). Each patient provided written informed consent for participation.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Glossary

Abbreviations

Abbreviations:

References