Cervical cancer remains a major health problem in Thailand and other lowand middle-income countries. The current standard treatment for locally advanced cervical cancer consists of conventionally fractionated external beam radiotherapy delivered over 5-7 weeks with concurrent chemotherapy, followed by brachytherapy. This prolonged treatment schedule requires frequent hospital visits and may limit access to care. Hypofractionated radiotherapy delivers a higher dose of radiation per treatment session while maintaining a comparable total radiation dose, thereby reducing the overall treatment duration. Preliminary studies suggest that hypofractionated chemoradiotherapy using modern radiotherapy techniques may provide similar disease control and acceptable toxicity compared with conventional treatment, while improving treatment convenience and reducing healthcare burden. This multicenter phase III randomized controlled trial aims to compare hypofractionated whole pelvic concurrent chemoradiotherapy with conventional chemoradiotherapy in patients with early-stage node-positive and locally advanced cervical cancer. The study will evaluate nodal control and overall survival, as well as tumor response, treatment-related toxicities, quality of life, and cost-effectiveness.

Cervical cancer remains one of the leading causes of cancer-related morbidity and mortality among women in Thailand and other low- and middle-income countries. Although improvements in cervical cancer screening programs and human papillomavirus (HPV) vaccination have reduced disease incidence, a substantial proportion of patients continue to present with locally advanced disease requiring definitive chemoradiotherapy. The current standard treatment for locally advanced cervical cancer consists of conventionally fractionated external beam radiotherapy (45-50.4 Gy delivered in 25-28 fractions) administered concurrently with platinum-based chemotherapy, followed by image-guided brachytherapy. This treatment approach requires daily hospital visits over approximately 5-7 weeks and may contribute to treatment burden, limited access to radiotherapy services, and prolonged overall treatment time. Hypofractionated radiotherapy shortens treatment duration by delivering a higher dose per fraction while maintaining an equivalent biologically effective dose. This strategy has become an accepted standard of care in several malignancies, including breast, prostate, and rectal cancers. Emerging evidence suggests that hypofractionated chemoradiotherapy for cervical cancer using modern techniques such as intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT), combined with image-guided adaptive brachytherapy, provides acceptable toxicity profiles and promising disease control outcomes. The phase II HYPOCx-iRex trial demonstrated comparable gastrointestinal toxicity and encouraging oncologic outcomes between hypofractionated and conventional chemoradiotherapy regimens. Additional prospective studies have reported favorable response rates, disease control, and acceptable treatmentrelated toxicities with hypofractionated approaches. Moreover, hypofractionated treatment may improve healthcare efficiency and reduce societal costs by decreasing the number of treatment visits. This multicenter phase III randomized controlled trial will compare hypofractionated whole pelvic concurrent chemoradiotherapy with conventional chemoradiotherapy in patients with early-stage node-positive and locally advanced cervical cancer. Participants will be randomized to receive either hypofractionated external beam radiotherapy or conventional fractionation, both delivered using IMRT/VMAT techniques with concurrent chemotherapy and image-guided adaptive brachytherapy. The primary outcomes are nodal control and overall survival. Secondary outcomes include tumor response, local and regional disease control, eventfree survival, treatment-related toxicities, quality of life, and cost-effectiveness.

The findings from this study are expected to provide high-level evidence regarding the efficacy, safety, and economic value of hypofractionated chemoradiotherapy and may support broader implementation of this treatment strategy in resource-constrained settings.

Inclusion Criteria:

1. Cancer of the uterine cervix considered suitable for curative treatment with definitive radio-(chemo)therapy including imaged-guided BT
2. Positive biopsy showing squamous-cell carcinoma, adenocarcinoma, or adeno-squamous cell carcinoma of the uterine cervix
3. Locally advanced staging according to FIGO 2018 and TNM guidelines (Stage IA1-IVA)
4. MRI of the pelvis at diagnosis is performed
5. MRI, CT, or PET-CT of the retroperitoneal space and abdomen at diagnosis is performed
6. MRI with the applicator in place at the time of (first) BT will be performed
7. GFR ≥ 50 mL/min
8. Patient informed consent

Exclusion Criteria:

1. Other primary malignancies except carcinoma in situ of the cervix and basal cell carcinoma of the skin
2. Small cell neuroendocrine cancer, melanoma and other rare cancers in the cervix
3. Metastatic disease beyond intervertebral disc L2/3 level
4. Previous pelvic or abdominal radiotherapy
5. Previous total or subtotal hysterectomy
6. Combination of preoperative radiotherapy with surgery
7. Patients receiving BT only
8. Patients receiving EBRT only
9. Patients receiving neo-adjuvant chemotherapy or other forms of antineoplastic treatment apart from weekly concomitant cisplatin (40 mg/m2).
10. Contra-indications to MRI
11. Contra-indications to BT