Cervical Cancer
Conditions
Keywords
Cervical Cancer, Hypofractionated Radiotherapy, Conventional Radiotherapy, Whole Pelvic Radiotherapy, Chemoradiotherapy, Brachytherapy
Brief summary
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.
Detailed description
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.
Interventions
RADIATIONHypofractionated Radiotherapy
Whole pelvic radiotherapy delivered using hypofractionation (2.2 Gy per fraction over 20 fractions) with IMRT.
RADIATIONConventional Radiotherapy
Whole pelvic radiotherapy delivered using conventional fractionation (1.8 Gy per fraction over 25 fractions) with IMRT.
Cisplatin-based concurrent chemotherapy administered intravenously at a dose of 40 mg/m² once weekly during external beam radiotherapy for 5 to 6 cycles.
PROCEDUREImage-guided Adaptive Brachytherapy
Image-guided adaptive brachytherapy delivered following external beam radiotherapy.
PROCEDUREiReX Optimization
Brachytherapy treatment planning optimized using iReX in addition to standard D2cc constraints.
PROCEDUREStandard D2cc Planning
Conventional brachytherapy treatment planning using standard D2cc constraints without iReX optimization.
Sponsors
Siriraj Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Acute Treatment-Related Toxicity | During treatment and up to 3 months after completion of radiotherapy | Incidence of acute treatment-related toxicity during radiotherapy and at 1- and 3-month follow-up after treatment, assessed using CTCAE version 5.0. |
| Incidence of Late (Chronic) Treatment-Related Toxicity | From 6 months up to 5 years after completion of radiotherapy | Incidence of late (chronic) treatment-related toxicity assessed at 6 and 12 months, and at 3 and 5 years after treatment using CTCAE version 5.0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Response Rate | Up to 12 months after completion of radiotherapy | Tumor response rate assessed after external beam radiotherapy and at 3-, 6-, and 12-month follow-up. |
| Quality of Life Assessed by EQ-5D-5L | During treatment and up to 5 years after completion of radiotherapy | Patient-reported quality of life assessed using the EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L) during treatment and at 1-, 3-, 6-, and 12-month, and 3- and 5-year follow-up. The EQ-5D-5L descriptive system assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression across 5 levels of severity. The EQ Visual Analog Scale (EQ-VAS) ranges from 0 to 100, with higher scores indicating better perceived health status. |
| Local Recurrence-free Survival | At 3 and 5 years after completion of radiotherapy | Time from completion of radiotherapy to local tumor recurrence. |
| Nodal Recurrence-free Survival | At 3 and 5 years after completion of radiotherapy. | Time from completion of radiotherapy to nodal recurrence. |
| Distant Metastasis-free Survival | At 3 and 5 years after completion of radiotherapy. | Time from completion of radiotherapy to distant metastasis. |
| Disease-specific Survival | At 3 and 5 years after completion of radiotherapy. | Time from completion of radiotherapy to death due to cervical cancer. |
| Overall Survival | At 3 and 5 years after completion of radiotherapy. | Time from completion of radiotherapy to death from any cause. |
| Correlation of Dosimetric Parameters With Tumor Control and Toxicity | During treatment and follow-up up to 5 years after completion of radiotherapy. | Exploratory analyses will assess the correlation between dosimetric parameters from brachytherapy treatment planning, including dose-volume histogram (DVH) metrics and iRex optimization values, and clinical outcomes, including local tumor control and incidence of treatment-related gastrointestinal and genitourinary toxicities assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. |
| High-risk Clinical Target Volume D90 Comparison Between iRex-oriented and Conventional Brachytherapy Planning | From treatment initiation through completion of brachytherapy treatment, an average of 4 weeks. | Comparison of high-risk clinical target volume (HR-CTV) D90 dose between iRex-oriented optimization and conventional brachytherapy planning. |
| Number of Brachytherapy Fractions Achieving Successful iRex Optimization | From treatment initiation through completion of brachytherapy treatment, an average of 4 weeks. | Number and percentage of brachytherapy fractions achieving successful iRex-oriented dose optimization according to predefined planning objectives. |
| Dose-Response Relationship Between iRex and Toxicity | During follow-up up to 5 years | Evaluation of the relationship between iRex values and treatment-related toxicity. |
| Incremental Cost-effectiveness Ratio per Quality-adjusted Life Year Between Hypofractionated and Conventional Radiotherapy | During treatment and follow-up up to 5 years after completion of radiotherapy. | Cost and utility data will be used to evaluate cost-effectiveness by calculating the incremental cost-effectiveness ratio (ICER) between hypofractionated and conventional radiotherapy. Uncertainty analyses will be performed using oneway sensitivity analysis, probabilistic sensitivity analysis, and threshold analysis. |
Countries
Thailand
Outcome results
None listed