This randomized clinical trial will evaluate whether adding spatially fractionated radiation therapy (SFRT) to definitive chemoradiotherapy improves outcomes in patients with locally advanced cervical cancer. Adult patients with FIGO 2018 stage IIB to IVA cervical cancer who are planned to receive definitive chemoradiotherapy will be randomly assigned in a 1:1 ratio to an SFRT group or a control group.
Both groups will receive external-beam radiation therapy, concurrent chemotherapy, and brachytherapy. Patients with pelvic wall, rectal, or bladder invasion may also receive immunotherapy as specified in the study protocol. In the experimental group, external-beam radiation therapy will begin with three fractions of SFRT, using a peak dose of 8 Gy per fraction and keeping the valley dose as low as reasonably achievable, generally no more than 3 Gy per fraction. Conventional fractionated external-beam radiation therapy will then begin within 1 to 3 days. Participants in the control group will receive conventional fractionated external-beam radiation therapy without SFRT.
The primary objective is to determine whether SFRT improves 3-year progression-free survival. Secondary objectives include objective response rate, treatment safety, overall survival, and the occurrence of an abscopal effect. Exploratory translational studies will evaluate tumor and peripheral blood immune characteristics when biospecimens are available and participants provide consent.
Age ≥18 years.
Histologically confirmed cervical cancer, including squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma.
FIGO 2018 stage IIB to IVA disease with primary tumor ≥4cm
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
Severe medical comorbidities that preclude the safe administration of radiotherapy.
Pregnancy or, for women of childbearing potential, inability to use effective contraception.
Parallel
Spatially Fractionated Radiation Therapy
RadiationSpatially fractionated external-beam radiation therapy will be delivered in three fractions before conventional fractionated radiation therapy. The prescribed peak dose is 8 Gy per fraction. The valley-to-peak dose ratio will be minimized, with the valley dose generally approximately one-third of the peak dose and usually no more than 3 Gy per fraction. Conventional fractionated external-beam radiation therapy will begin within 1 to 3 days after completion of SFRT.
standard of care
RadiationParticipants in the control arm will undergo conventional concurrent chemoradiotherapy followed by brachytherapy. Participants in the SFRT arm will first receive SFRT, then receive the same chemoradiotherapy and brachytherapy regimen. For both arms, the decision to add concurrent and consolidation immunotherapy to the backbone treatment will be made according to the latest clinical guidelines and standard practice at the time of treatment.
3-Year Progression-Free Survival (PFS) Rate
The percentage of participants who are alive without disease progression at 3 years after randomization. Progression-free survival is defined as the time from randomization to the first documented recurrence or progression at any site or death from any cause, whichever occurs first.
Objective Response Rate (ORR) at 3 Months After Radiotherapy
Objective response rate is defined as the percentage of evaluable participants who achieve a complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), based on post-treatment imaging assessment.
Incidence of Acute Adverse Events
The number and percentage of participants experiencing adverse events from the first day of study treatment through 90 days after completion of radiotherapy. Acute adverse events will be graded according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0).
Incidence of Late Radiation Toxicity
The number and percentage of participants experiencing late radiation-related toxicities by grade. Late toxicity is defined as toxicity occurring more than 90 days after completion of radiotherapy and will be assessed using the Radiation Therapy Oncology Group late radiation morbidity scoring criteria.
Overall Survival (OS)
Overall survival is defined as the time from randomization to death from any cause. Participants who are alive at the last follow-up will be censored at the date of their last known follow-up.
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