Severe lymphopenia is a common complication of extended-field radiotherapy in cervical cancer, significantly impacting immune function and clinical outcomes. This study aims to evaluate whether proton therapy, with its superior dose distribution, can reduce lymphopenia and improve survival and toxicity profiles compared to photon therapy.

This study is a prospective, observational cohort study designed to evaluate the effects of proton therapy and photon therapy in patients with stage IIIC1 or IIIC2 cervical cancer undergoing extended-field radiotherapy. Primary data collection will include clinical outcomes, radiotherapy-related toxicities, lymphocyte counts, and immune cell subsets (e.g., CD4, CD8, CD19, and CD16+56), measured at baseline, during treatment, and post-treatment. Secondary data collection will involve tissue banking for future translational research projects, including serum, plasma, and whole blood for DNA analysis.

The study will be conducted in two tertiary cancer centers (CGMH and NTUCC), with individual patient participation proton or photon treatment approximately 9 weeks, followed by an additional five years for long-term follow-up to assess survival outcomes and late toxicities. This design enables robust comparison of the therapeutic impact of proton and photon therapies on clinical and immunological endpoints, providing evidence to guide personalized treatment decisions in cervical cancer.

Inclusion Criteria:

• Histologically confirmed cervical cancer, stage ≥ IIIC.
• Age between 20 and 85 years.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Eligible for extended-field radiotherapy as determined by the treating physician.
• Induction chemotherapy with paclitaxel and carboplatin is allowed if the duration is ≤ 6 weeks or ≤ 2 cycles.
• RT alone, or concurrent single-agent chemotherapy with weekly cisplatin or carboplatin during radiation therapy is allowed, while the use of any other concurrent antineoplastic agents is prohibited.
• Consolidative chemotherapy or immunotherapy after radiation therapy is allowed.

Exclusion Criteria:

• Prior history of pelvic or abdominal radiotherapy.
• Presence of distant metastases or other active malignancies within the past 5 years, excluding non-melanoma skin cancer.
• Severe comorbid conditions, such as uncontrolled diabetes, cardiovascular disease, or autoimmune disorders, that may interfere with treatment or study participation.
• Pregnancy or breastfeeding at the time of enrollment.
• Psychiatric or social conditions that would limit compliance with study requirements or follow-up.