Combined chemoradiotherapy and pelvic high-frequency focused hyperthermia for locally advanced cervical cancer: efficacy and incidence of acute radiation proctitis

1. Introduction

Cervical cancer is one of the most common gynecological malignancies in China, with incidence and mortality rates second only to those of breast cancer, posing a significant threat to women’s health [1]. For patients with locally advanced disease, the “NCCN Clinical Practice Guidelines in Oncology for Cervical Cancer (2022 version)” recommend concurrent chemoradiotherapy combined with intracavitary brachytherapy as a key radical treatment strategy [2]. However, this regimen is frequently associated with dose-limiting toxicities, most notably acute radiation proctitis (ARP). Approximately 75% of patients develop ARP-related symptoms, such as diarrhea, abdominal pain, and tenesmus, within 1–2 weeks of initiating radiotherapy. In severe cases, patients may experience gastrointestinal bleeding or even bowel perforation, which significantly impairs treatment compliance and reduces quality of life. Although multimodal comprehensive treatment (e.g., combining neoadjuvant chemotherapy, radical surgery, and adjuvant chemoradiotherapy) has become an important strategy for improving the prognosis of locally advanced cervical cancer (LACC), a clinical observation published in the European Society of Gynaecological Oncology (EJGO) indicated that even with sustained locoregional control in the abdomen and pelvis, distant metastases (e.g., to the lungs, heart, or posterior cranial fossa) remained a primary cause of treatment failure and patient mortality [3]. Therefore, identifying effective and safe interventions to prevent and mitigate ARP is crucial for ensuring the successful completion of chemoradiotherapy, improving patient prognosis, and enhancing quality of life.

Solid tumors in cervical cancer frequently contain hypoxic regions, which contribute to radioresistance and compromise treatment efficacy [4]. Research has demonstrated that hyperthermia not only directly targets and destroys radioresistant tumor cells in the S phase, but also enhances radiosensitivity by increasing tumor blood perfusion and alleviating hypoxia within the tumor microenvironment [5]. In addition, hyperthermia disrupts the function of key DNA damage repair proteins, particularly those in the Ataxia Telangiectasia Mutated/Ataxia Telangiectasia and Rad3-related (ATM/ATR) signaling pathway, thereby amplifying the cytotoxic effects of radiotherapy. It also induces the expression of heat shock proteins (HSPs), which play a pivotal role in activating dendritic cells and cytotoxic T lymphocytes. This immune activation can elicit an abscopal effect, further enhancing the systemic antitumor response and potentiating the overall efficacy of radiotherapy [6].

In recent years, hyperthermia has been widely integrated into the comprehensive management of various malignancies, including cervical cancer [7] and head and neck cancer [8], now emerging as a significant therapeutic modality alongside surgery, radiotherapy, chemotherapy, and immunotherapy. To improve local tumor control in patients with LACC, the integration of CCRT with pelvic high-frequency focused hyperthermia is gaining clinical traction as a promising and practical therapeutic approach [9]. This combined modality offers multiple advantages. Hyperthermia, on one hand, allows for a reduction in the required radiation dose while mitigating the development of thermotolerance. On the other hand, it enhances the tissue permeability of chemotherapeutic agents, leading to increased intratumoral drug concentrations and thereby amplifying their antitumor efficacy. Pelvic high-frequency focused hyperthermia acts synergistically with chemoradiotherapy through a combination of physical, cellular, and microenvironmental mechanisms, as illustrated in Fig. 1. Additionally, this regimen effectively prevents and alleviates radiotherapy-related toxicities, such as radiation-induced enteritis, thereby reducing instances of radiotherapy intolerance associated with these complications. The synergistic interplay between these modalities may enhance therapeutic efficacy by promoting both radiosensitization and chemosensitization.

Fig. 1.Schematic diagram illustrating the mechanism of action of high-intensity focused hyperthermia in the pelvic region.

This study, therefore, aimed to evaluate the clinical outcomes of combining pelvic high-frequency focused hyperthermia with CCRT in patients with LACC, with particular emphasis on its potential to reduce the incidence and severity of ARP. The findings may offer evidence-based insights for optimizing therapeutic strategies in this patient population.

2. Materials and methods

2.2 Treatment protocol

Patients in the control group received standard concurrent chemoradiotherapy (CCRT), which included External Beam Radiation Therapy (EBRT), High Dose Rate (HDR) intracavitary brachytherapy, and weekly cisplatin chemotherapy. The treatment protocol was as follows:

(1) Radiotherapy: VMAT was employed for pelvic EBRT. Patients were positioned supine and immobilized with a thermoplastic mask for Computed Tomography (CT) simulation. The acquired CT images were directly utilized in the following critical procedures: Initially, physicians precisely delineated the tumor target volume and organs at risk in the planning system based on these CT images. Subsequently, dose calculation and optimization were performed using the same CT dataset, ultimately generating the final VMAT treatment plan. The Clinical Target Volume (CTV) was delineated based on international consensus guidelines (e.g., European Society for Radiotherapy & Oncology) and included the common iliac, bilateral external iliac, internal iliac, obturator, and presacral lymph nodes, as well as the cervix, uterine corpus, parametria, and vagina. The superior border was set at the L4–L5 vertebral level, and the inferior border extended 3–4 cm below the vaginal fornix. Based on the clinical practice at the time of treatment, for patients with tumor invasion of the lower third of the vagina, the CTV was expanded to include the bilateral inguinal lymph nodes. The Planning Target Volume (PTV) received a dose of 45–50.4 Gy in 25–28 fractions, at 1.8–2.0 Gy per fraction, administered five times per week. A simultaneous integrated boost of 59.92 Gy in 28 fractions was delivered to the primary gross tumor volume and any clinically diagnosed metastatic pelvic or retroperitoneal lymph nodes. Radiotherapy was delivered using an Elekta Axesse linear accelerator, operating at 6–10 MV photon energy with 1–3 arcs [10]. Rectal dose constraints during EBRT were as follows: For conventional EBRT: Rectum V45–50 ≤40%. For precision techniques like Intensity-Modulated Radiation Therapy (IMRT)/VMAT: Rectum V40 <55%, V45 <50%.

(2) Intracavitary Brachytherapy: HDR intracavitary brachytherapy was performed following the completion of EBRT, using an Iridium-192 (¹⁹²Ir) source. The brachytherapy protocol was as follows: ① Fractionation: A standard HDR regimen of 5 fractions was used, delivering 6 Gy per fraction to the High-Risk Clinical Target Volume (HR-CTV), totaling 30 Gy. For patients with residual disease or large tumor volume after EBRT, plan optimization ensured a Dose 90% equivalent dose in 2 Gy fraction (D90 EQD2) to the HR-CTV of ≥85 Gy. ② Interval: Treatments were typically administered twice per week, with a minimum interval of 48 hours between fractions to allow for normal tissue repair. ③ Applicator Type: An intrauterine tandem combined with ovoids (or a ring) applicator was used for all patients to adapt to the uterine anatomy and cover the cervix, parametria, and upper vaginal lesions. None of the enrolled patients had a history of hysterectomy, and their tumors were confined to areas effectively covered by intracavitary applicators; therefore, interstitial brachytherapy was not employed. Interstitial techniques would have been considered for extensive parametrial invasion or pelvic sidewall involvement beyond the coverage of intracavitary applicators. ④ Technique: CT-based image-guided brachytherapy (IGBT) was performed before each fraction. Prior to each fraction, CT simulation was performed. The HR-CTV, Intermediate-Risk CTV (IR-CTV), and Organs at Risk (OARs: rectum, bladder, small bowel, sigmoid colon) were delineated on CT images. Dose calculation and plan optimization were based on three-dimensional (3D) inverse planning, and dose distribution was evaluated using dose-volume histograms (DVHs). The treatment plan aimed to meet the prescribed dose for HR-CTV D90 while adhering to the following OAR dose constraints (EQD2): rectum Dose to the most irradiated 2 cubic centimeters (D2cc) ≤65–70 Gy, bladder D2cc ≤80–90 Gy, and small bowel/sigmoid colon D2cc ≤70–75 Gy. ⑤ Procedure: The ¹⁹²Ir source was afterloaded through the applicator channels into the pre-positioned tandem and ovoids. Under computer control, the source dwelled at predetermined positions for calculated times to deliver the precise dose before being automatically retracted.

(3) Concurrent Chemotherapy: Concurrent intravenous cisplatin chemotherapy was administered weekly during radiotherapy at a dose of 40 mg/m², for a total of 4–6 cycles. Dose constraints for the rectum during brachytherapy were rectum D2cc ≤65–75 Gy (EQD2). For single-fraction physical dose limits, if the remaining tolerable dose after EBRT was 30 Gy (e.g., after 45 Gy EBRT), the recommended single physical dose to the rectum during HDR brachytherapy should not exceed 4.0–4.2 Gy.

Patients in the experimental group received pelvic hyperthermia in addition to the standard concurrent chemoradiotherapy regimen described for the control group. Hyperthermia was delivered using the US Pyrexar BSD-2000 phased-array focused radiofrequency hyperthermia system (Salt Lake City, UT, USA), operating at a frequency of 75–120 MHz. Treatments were administered within 1 hour after each EBRT session, three times per week, for 60 minutes per session, with the target area core temperature maintained between 40–43 °C. The hyperthermia protocol included: (1) Patient documentation and treatment planning. Pretreatment pelvic CT or Magnetic resonance imaging (MRI) was used to determine tumor location. The coordinates (X, Y axes) on the transverse plane and the body’s laterolateral and anteroposterior dimensions of the body were measured. Computer-generated thermal field distribution maps displayed the effective temperature range, thermal dose, power/time (W/t), and temperature/time (T/t) values at the target center. Treatment parameters (frequency, amplitude, phase, target temperature, and duration) were set accordingly. The BSD-2000 system incorporated a circulating water cooling system with an initial temperature of 30 °C, which could be adjusted 1–2 hours before treatment to ensure optimal patient comfort and target temperature achievement while preventing skin burns. (2) Patient positioning and system adjustment. Patients were positioned supine on the treatment platform, which consisted of an adjustable high-strength mesh stretcher and radiators with attached water bags. The treatment area was exposed and disinfected with 75% alcohol. Temperature probes were placed at the center of the surface projection of the lesion and securely fixed. The treatment bed was elevated to align the radiator’s focal point with the transverse plane of the target. Water bags were filled to ensure proper coupling between the radiator and body surface. (3) Treatment initiation. The initial power was set at 300–400 W. Computer-controlled non-invasive temperature monitoring was used throughout the session [11]. Parameters were adjusted based on real-time temperature data and patient feedback to maintain the target temperature at 40–43 °C for 60 minutes per session, administered 3 times weekly. (4) Treatment monitoring. Patients were closely observed for consciousness level, vital signs, and temperature changes (with surface temperature limited to approximately 43 °C). Subjective thermal sensations and discomfort were regularly assessed. The circulating water cooling system was activated for surface temperature control. Patients were instructed to practice thoracic breathing to reduce respiratory discomfort caused by abdominal water bag enclosure. (5) Post-treatment care. The treated skin was examined for erythema, blistering, or other signs of thermal injury. Cold compresses and topical burn ointments were applied when necessary. To ensure precision and safety, an individualized hyperthermia plan was developed for each patient.

Fig. 2A–D shows the real-time control interface during treatment, monitoring key parameters such as target temperature and power output. Fig. 2E displays the simulated thermal field distribution generated by the system, ensuring the precise delivery of effective thermal dose to the target volume. This workflow, from planning to execution, demonstrates the precision and conformality of this technology, as illustrated in Fig. 2.

Fig. 2.BSD-2000 hyperthermia system. (A–D) Real-time treatment control interface. (E) Computer-simulated thermal field distribution.

3. Results

3.4 Comparison of 2-year PFS and 3-year OS between groups

Kaplan-Meier analysis demonstrated significantly superior outcomes in the experimental group compared with controls, with higher 2-year PFS rates (44.44% vs. 26.47%; log-rank χ² = 9.139, p = 0.003) and improved 3-year OS rates (61.11% vs. 47.06%; log-rank χ² = 7.550, p = 0.006) (Fig. 3). Furthermore, compared with control group, the experimental group exhibited prolonged median PFS (18 (16–19) months vs. 11 (7–14) months) and median OS (29 (22–35) months vs. 18 (13–22) months), representing absolute increases of 7 months and 9 months, respectively.

Fig. 3.Kaplan-Meier survival curves comparing treatment outcomes between control and experimental groups. (A) Progression-free survival (PFS). (B) Overall survival (OS).

Cox proportional hazards regression analysis (with group assignment: control group = 1, experimental group = 0) further confirmed these findings. The hazard ratio (HR) for PFS in the experimental group was 0.3574, corresponding to an approximately 64.26% reduction in the risk of disease progression (HR = 0.3574; 95% CI: 0.0652–0.6821; p = 0.002). Similarly, the hazard ratio for OS was 0.4627, indicating an approximately 53.73% decrease in the risk of death (HR for OS = 0.4627, 95% CI: 0.2271–0.9425, p = 0.034).

4. Discussion

Cervical cancer remains one of the most prevalent malignancies affecting women worldwide and represents the most common gynecologic cancer in China. More than half of patients are diagnosed at a locally advanced stage, posing a serious threat to women’s health and overall survival [13]. Concurrent chemoradiotherapy (CCRT) has been established as the standard of care and cornerstone treatment for LACC; however, despite therapeutic advancements, the 5-year survival rate continues to remain below two-thirds [14]. Due to its relatively fixed anatomical position within the pelvis, the rectum is highly susceptible to radiation exposure during pelvic radiotherapy, predisposing it to radiation-induced injury and the development of radiation proctitis. Although brachytherapy effectively delivers a high localized radiation dose to the tumor target volume, it also concentrates the radiation field, thereby markedly increasing rectal dose exposure and, consequently, the risk of developing radiation proctitis. Clinical observations indicate that early symptoms of ARP typically emerge within 1–2 weeks after radiotherapy, with reported incidence rates varying widely (16.5%–48%) [15, 16, 17]. This wide variability may be attributed to differences in radiotherapy protocols, techniques, and the lack of standardized diagnostic criteria for ARP in China. The occurrence of ARP compromises the continuity of radiotherapy, often prolonging or interrupting treatment courses, ultimately impairing therapeutic efficacy. Compared with conventional IMRT, VMAT shortens treatment duration, reduces monitor units, and offers superior target dose homogeneity and enhanced normal tissue sparing.

Hyperthermia has gained widespread clinical application in recent years as an effective adjunctive therapy for various malignancies. Its fundamental principle involves utilizing physical energy (e.g., radiofrequency or microwaves) to heat tumor tissues, accumulating thermal effects that elevate localized or systemic temperatures to therapeutic levels for a sustained duration, thereby achieving tumor ablation through direct cytotoxicity and secondary effects [18]. The BSD-2000 phased-array focused deep hyperthermia system represents a significant technological advancement over conventional devices. It integrates a sophisticated 3D treatment planning system, multi-element circumferential radiators, a circulating water-cooling coupling mechanism, and advanced thermometry capabilities. These features collectively enable precise energy deposition, non-invasive operation, and streamlined clinical workflows, establishing it as a form of precision conformal hyperthermia. Treatment protocols are individualized according to tumor size, depth, and anatomical location. Accurate target delineation, optimized radiation frequency/amplitude, and real-time parameter adjustments during thermoradiotherapy ensure effective and safe delivery of therapeutic heat while minimizing damage to surrounding normal tissues. In this study, the application of pelvic high-frequency focused hyperthermia in combination with concurrent chemoradiotherapy significantly delayed the onset of acute radiation proctitis (ARP), with the median time to occurrence extended from day 13 post-radiotherapy in the control group to day 19 in the experimental group. Furthermore, combined hyperthermia markedly reduced the severity of ARP. These findings are consistent with previous hyperthermia studies in the field of gynecologic oncology. For instance, one clinical study [19] demonstrated that combining weekly paclitaxel/carboplatin chemotherapy with abdominal radiofrequency hyperthermia in 22 patients with advanced ovarian cancer resulted in no unexpected or grade III–IV acute toxicities throughout the 18-week treatment period, indicating favorable tolerability and feasibility of this combined regimen. A meta-analysis [20] confirmed that, in patients with LACC, the addition of regional hyperthermia to radiotherapy significantly improved both the complete response rate and locoregional control rate, without increasing the incidence of severe acute or late toxicities. These findings suggest that the combination of hyperthermia, chemotherapy, and radiotherapy may represent a highly promising strategy for enhancing treatment response and survival outcomes. This enhanced oxygenation not only augments the cytotoxic efficacy of radiotherapy through the oxygen enhancement effect, but also supports the proliferation and repair of normal tissues, such as the rectal mucosa, thus helping to mitigate radiation-induced injury [21]. On the other hand, hyperthermia may reduce the incidence of acute toxicities, such as ARP, through several biological mechanisms. First, the thermal effects of hyperthermia inhibit the release of pro-inflammatory cytokines, thereby attenuating inflammatory responses and reducing the risk of radiation-induced proctitis [22]; Second, hyperthermia activates immune cells within the tumor microenvironment, enhancing systemic immune function and alleviating the adverse effects associated with chemoradiotherapy [23]. Third, hyperthermia reduces thermotolerance in tumor cells, improving hyperthermia efficacy and thereby enhancing the capacity for repair of radiation injury [24]. Collectively, these mechanisms contribute to the clinical benefit of pelvic high-frequency focused hyperthermia in lowering both the incidence and severity of ARP.

The role of thermoradiotherapy in cervical cancer management has been well established. Concurrent chemoradiotherapy combined with hyperthermia demonstrates higher response rates and overall survival, with significantly reduced recurrence rates without increasing toxicities [25, 26]. Pelvic high-frequency focused hyperthermia may markedly enhance tumor radiosensitivity and chemotherapeutic efficacy by modulating the tumor microenvironment, thereby improving locoregional control. The findings of this study demonstrated that the combined modality (pelvic hyperthermia + VMAT + intracavitary brachytherapy + platinum-based chemotherapy) not only delayed the onset of ARP, but also reduced its severity, mitigating treatment-related adverse effects while improving short-term clinical outcomes. Notably, patients exhibited significantly improved quality of life, with 2-year PFS increasing to 44.44%, and median PFS extended by 7 months and median OS by 9 months.

The results of this study align with previous findings on hyperthermia in gynecologic oncology. For example, a basic research study published in the “International Journal of Molecular Sciences” [27] showed that even mild (39–40 °C) or moderate hyperthermia significantly enhanced the cytotoxic effects of the anticancer drugs cisplatin and tamoxifen on ovarian cancer cells in vitro. The mechanism primarily involved the downregulation of anti-apoptotic gene expression, thereby markedly promoting cancer cell apoptosis and reducing cell viability. Their study provided molecular-level evidence supporting hyperthermia as a potential sensitizing modality in combination therapy for ovarian cancer. Furthermore, the Dutch Deep Hyperthermia Trial [28], with 12 years of long-term follow-up, confirmed that for LACC, the addition of hyperthermia to radiotherapy consistently and significantly improved long-term locoregional control rates (from 37% to 56%) and overall survival (from 20% to 37%), without increasing severe late toxicities. The study demonstrated that hyperthermia combined with radiotherapy is an effective and safe treatment strategy, offering an important therapeutic option particularly for patients unable to tolerate chemotherapy. Hyperthermia not only influences cell cycle redistribution, enhancing radiation-induced mitotic block and arresting most cells in S and G2 phases, leading to protein denaturation and inhibition of the repair of radiation-induced DNA double-strand breaks [29], it also induces heat shock proteins (HSPs) as “danger signals”, promoting dendritic cell maturation and antigen presentation, and enhancing cluster of differentiation 8 positive (CD8⁺) T cell-mediated tumor cytotoxicity. These effects may help control micrometastases, boost immune function, and reduce the adverse effects of chemoradiotherapy [30]. These findings highlight the synergistic sensitizing effects of hyperthermia, offering promising avenues for the optimization of comprehensive treatment strategies in LACC and demonstrating significant clinical application value.

Previous authoritative studies (such as the Dutch Deep Hyperthermia Trial [28]) and meta-analyses [20] primarily established the value of hyperthermia in improving long-term locoregional control and overall survival. In contrast, the present study shifts the focus to an earlier clinical outcome, representing the first to systematically demonstrate the prominent role of pelvic high-frequency focused hyperthermia in preventing and mitigating ARP induced by concurrent chemoradiotherapy. This study not only reports a significant reduction in ARP incidence (19.44% vs. 44.12%), but also highlights clinical benefits, such as the delayed onset of ARP (median time postponed from 13 to 19 days) and reduced severity (no grade III/IV injuries in the experimental group). These findings provide high-quality evidence supporting improvements in patients’ quality of life and treatment compliance during therapy. While prior research has typically explored hyperthermia in combination with radiotherapy or its role as a chemosensitizer [19, 27], this study innovatively incorporates hyperthermia into the current standard treatment regimen for LACC namely, the established triple-modality approach consisting of VMAT-based radiotherapy, intracavitary brachytherapy, and weekly cisplatin-based concurrent chemotherapy. Within this context, our study confirms that the addition of hyperthermia not only maintains its traditional “sensitizing” effect (manifested as prolonged PFS and OS), but also highlights its independent protective effect on normal tissues, clarifying its dual value of “reducing toxicity and enhancing efficacy” within an intensified treatment protocol, rather than acting merely as a simple efficacy enhancer. Although basic research has suggested that hyperthermia may exert its effects through mechanisms such as improving microcirculation and suppressing inflammation, this study is the first to clinically demonstrate a significant reduction in a specific acute toxicity ARP. The detailed ARP grading data provided herein offer robust clinical evidence supporting the hypothesis that “hyperthermia can alleviate radiation-induced injury”, effectively bridging basic mechanistic research with clinical outcomes and pointing towards important future directions for exploring its molecular mechanisms. To further contextualize the contribution of this study within the broader field, Table 4 (Ref. [19, 20, 27, 28]) presents a systematic comparison of recent major clinical studies on hyperthermia combined with concurrent chemoradiotherapy for gynecologic cancers, alongside the key outcome measures of the present study.

However, this study has several limitations. First, as a single-center retrospective study with a limited sample size (n = 70) and non-randomized grouping, although baseline characteristics were balanced, potential selection bias may exist. Second, due to the small sample size, it was not feasible to perform multivariate Cox regression analyses to adjust for potential confounding variables or to conduct adequately powered subgroup analyses (e.g., by tumor grade or nodal status). Third, the absence of measurements for mechanism-related biological markers, such as inflammatory cytokines and heat shock proteins, restricts the findings to the level of clinical observation rather than mechanistic validation. Fourth, the follow-up period was limited to 3 years, lacking data on long-term toxicities, including chronic radiation-injuries. Finally, the high cost of hyperthermia equipment presents practical challenges for widespread implementation, particularly in low- and middle-income settings, underscoring the need for future health economic evaluations to assess its cost-effectiveness and feasibility.

5. Conclusions

The addition of pelvic high-frequency focused hyperthermia to standard concurrent chemoradiotherapy significantly reduces the incidence and severity of ARP in patients with LACC and shows potential for improving survival outcomes. This combined strategy holds significant clinical value. Future studies should include multicenter, randomized controlled trials to provide higher-level evidence and explore translational endpoints, such as heat shock protein expression, circulating tumor DNA, and specific immune cell subsets as predictive biomarkers of treatment efficacy. These findings are hypothesis-generating and warrant validation in multicenter randomized trials.

Availability of data and materials

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Author contributions

QY—designed the study and carried them out. QY, KZ, LHW and RJT—supervised the data collection, analyzed the data, interpreted the data. QY, HFS and WXD—prepared the manuscript for publication and reviewed the draft of the manuscript. All authors have read and approved the manuscript.

Ethics approval and consent to participate

Ethical approval was obtained from the Ethics Committee of Hangzhou Cancer Hospital (Approval no. HZCH-2023-018). The Ethics Committee granted a waiver for the requirement of obtaining informed consent.

Acknowledgment

Not applicable.

Funding

This work was supported by Hangzhou Science and Technology Development Plan (Grant No. 2020ZDSJ0552) and Zhejiang Provincial Medical and Health Science and Technology Plan Project (Grant No. 2022KY980).

Conflict of interest

The authors declare no conflict of interest.