Hypofractionated Whole Pelvic Chemoradiotherapy With iRex Optimization in Cervical Cancer

HYPOfractionated Whole Pelvic Concurrent Chemoradiotherapy in Cervical (Cx) Cancer With "Indirect Excess Dose Volume Ratio (iRex)" - Optimized Image Guided Adaptive Brachytherapy (HYPOCx-iRex Trial) : A Phase II Non-inferiority Randomized Controlled Trial

This study is a randomized controlled trial designed to compare hypofractionated whole pelvic radiotherapy with conventional radiotherapy in patients with cervical cancer undergoing concurrent chemoradiotherapy.

Hypofractionated radiotherapy delivers a higher dose per treatment over a shorter overall treatment time, which may reduce the number of hospital visits and improve treatment convenience for patients. Conventional radiotherapy requires more treatment sessions over a longer period.

The purpose of this study is to evaluate whether hypofractionated radiotherapy is as safe and effective as conventional radiotherapy. The primary outcomes focus on treatment-related toxicity, while secondary outcomes include tumor response, survival outcomes, quality of life, and treatment-related factors.

In addition, this study will evaluate a novel planning approach called the indirect excess dose volume ratio (iRex) to optimize brachytherapy planning and potentially reduce radiation-related side effects.

Cervical cancer remains a significant global health burden, particularly in low- and middle-income countries. Standard treatment for locally advanced cervical cancer consists of conventional fractionated radiotherapy combined with concurrent chemotherapy, followed by brachytherapy. However, conventional radiotherapy requires prolonged treatment duration, which may negatively impact patient compliance, healthcare resource utilization, and treatment outcomes.

Hypofractionated radiotherapy delivers a higher dose per fraction while maintaining a comparable total biological dose, thereby reducing the overall treatment time. Shortening treatment duration may improve tumor control based on radiobiological principles and reduce patient burden, including travel and treatment-related costs.

Previous studies suggest that hypofractionated radiotherapy may provide comparable oncologic outcomes to conventional radiotherapy, with acceptable toxicity profiles. However, high-quality randomized evidence remains limited, particularly using modern radiotherapy techniques such as intensity-modulated radiotherapy (IMRT) and image-guided adaptive brachytherapy (IGABT).

This study is a Phase II randomized controlled trial designed to evaluate the safety and feasibility of hypofractionated whole pelvic radiotherapy compared with conventional fractionation. Patients will be randomized to receive either hypofractionated or conventional external beam radiotherapy, both combined with concurrent chemotherapy and followed by brachytherapy.

In addition, this study incorporates a novel dosimetric parameter, the indirect excess dose volume ratio (iRex), to optimize brachytherapy planning. The use of iRex in combination with standard dose constraints may improve spatial dose control and reduce radiation-induced toxicity.

The primary objective is to assess treatment-related toxicity, while secondary objectives include tumor response, survival outcomes, quality of life, dosimetric parameters, and cost-effectiveness. This study aims to provide evidence supporting a shorter, more efficient radiotherapy regimen without compromising safety or efficacy.

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. Staging according to FIGO 2018 and TNM guidelines
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