Hypofractionated Chemoradiotherapy for Cervical Cancer

Cervical cancer remains a major contributor to cancer-related morbidity and mortality among women in low- and middle-income countries, including Thailand. Despite advancements in screening programs and human papillomavirus (HPV) vaccination, a substantial proportion of patients present with locally advanced disease necessitating definitive concurrent chemoradiotherapy.

The established standard of care for locally advanced cervical cancer consists of conventionally fractionated external beam radiotherapy (45 to 50.4 Gy delivered in 25 to 28 fractions) administered concurrently with platinum-based chemotherapy, followed by image-guided adaptive brachytherapy. However, this extended 5-to-7-week regimen imposes significant logistical and financial burdens on patients and healthcare infrastructure, contributing to prolonged overall treatment times, institutional capacity constraints, and restricted access to radiation oncology services. Although hypofractionated radiotherapy has established efficacy and safety in the treatment of breast, prostate, and rectal malignancies, high-level prospective evidence validating its application alongside concurrent chemotherapy in cervical cancer, particularly in the setting of extended-field irradiation, remains limited due to concerns regarding exacerbated gastrointestinal and hematologic toxicities.

To address these therapeutic constraints of conventional fractionation, our group conducted the Phase II HYPOCx-iRex trial (TCTR20210812003). Findings from the HYPOCx-iRex study provided essential clinical proof-of-concept, demonstrating that hypofractionated chemoradiotherapy delivered via advanced delivery techniques, such as IMRT/VMAT with adaptive brachytherapy, achieves acceptable gastrointestinal toxicity rates and promising short-term disease control relative to historical conventional benchmarks.

Building upon the foundation of the Phase II HYPOCx-iRex trial (TCTR20210812003), this multicenter Phase III randomized controlled superiority trial is designed to evaluate this hypofractionated paradigm. Crucially, this trial seeks to address the persistent lack of prospective evidence regarding the safety, feasibility, and oncologic efficacy of hypofractionated extended-field radiotherapy combined with concurrent platinum-based chemotherapy.

In this trial, patients with early-stage node-positive or locally advanced cervical cancer will be randomized to receive either hypofractionated or conventionally fractionated external beam radiotherapy, both administered using high-precision IMRT/VMAT techniques with concurrent chemotherapy and image-guided adaptive brachytherapy. The primary endpoints are nodal control and overall survival. Secondary endpoints encompass tumor response rate, locoregional control, event-free survival, acute and late toxicities, quality of life, and health economic cost-effectiveness. The trial's findings are anticipated to generate high-level clinical evidence capable of demonstrating superior therapeutic and operational value, mitigating treatment delays, and establishing a more accessible, resource-efficient treatment standard.

Inclusion criteria

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

Exclusion criteria

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