Hypofractionated Chemoradiotherapy for Cervical Cancer

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.

• Tumor Response Rate [Time frame: Up to 12 months after completion of radiotherapy]
• Local Recurrence-free Survival [Time frame: At 3 and 5 years after completion of radiotherapy]
• Pelvic Recurrence-free Survival [Time frame: At 3 and 5 years after completion of radiotherapy]
• Para-aortic Recurrence-free Survival [Time frame: At 3 and 5 years after completion of radiotherapy]
• Locoregional Recurrence-free Survival [Time frame: At 3 and 5 years after completion of radiotherapy]
• Distant Metastasis-free Survival [Time frame: At 3 and 5 years after completion of radiotherapy]
• Event-free Survival [Time frame: Up to 5 years after completion of radiotherapy]
• Incidence of Acute Treatment-related Toxicity [Time frame: During treatment and up to 3 months after completion of radiotherapy]
• Incidence of Late (Chronic) Treatment-related Toxicity [Time frame: From 6 months up to 5 years after completion of radiotherapy]
• Quality of Life Assessed by EQ-5D-5L [Time frame: During treatment and up to 5 years after completion of radiotherapy]
• Incremental Cost-effectiveness Ratio per Quality-adjusted Life Year Between Hypofractionated and Conventional Radiotherapy [Time frame: During treatment and follow-up up to 5 years after completion of radiotherapy.]