Spatially Fractionated Radiation Therapy for Locally Advanced Cervical Cancer

This is an investigator-initiated, randomized, parallel-group clinical trial evaluating spatially fractionated radiation therapy in patients with locally advanced cervical cancer. A total of 126 participants with histologically confirmed FIGO 2018 stage IIB to IVA cervical cancer will be enrolled and randomly assigned in a 1:1 ratio to the experimental SFRT group or the control group.

Participants in both groups will receive definitive treatment consisting of external-beam radiation therapy, concurrent chemotherapy, and brachytherapy. Patients with pelvic wall, rectal, or bladder invasion will additionally receive immunotherapy as specified by the protocol. Target-volume coverage and normal-tissue dose constraints will follow the same standards in both treatment groups.

In the experimental group, external-beam radiation therapy will begin with three fractions of spatially fractionated radiation therapy. The peak dose will be 8 Gy per fraction. The valley-to-peak dose ratio will be kept as low as reasonably achievable, 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 1 to 3 days after SFRT. The higher radiation dose within selected intratumoral regions constitutes the main difference between the experimental and control groups.

The primary endpoint is 3-year progression-free survival. Secondary endpoints include objective response rate according to RECIST version 1.1, acute and late treatment-related toxicity, overall survival, and abscopal effect rate. Optional translational analyses will investigate changes in tumor PD-L1 expression, tumor and peripheral blood immune-cell subsets, and transcriptomic characteristics.

• Spatially Fractionated Radiation Therapy (Radiation), also known as SFRT: Spatially 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 (Radiation): Participants 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.

Primary outcomes

• 3-Year Progression-Free Survival (PFS) Rate [From randomization to 3 years after randomization]: 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.

Secondary outcomes

• Objective Response Rate (ORR) at 3 Months After Radiotherapy [3 months after completion of 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 [From the first day of treatment through 90 days after completion of radiotherapy]: 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 [From more than 90 days after completion of radiotherapy through 5 years after randomization]: 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) [From randomization to death from any cause, assessed up to 5 years]: 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.

Sex: Female, ages: 18 Years to any

Inclusion Criteria:

* 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.
* Planned to receive definitive chemoradiotherapy.
* Able and willing to provide written informed consent.

Exclusion Criteria:

* Severe medical comorbidities that preclude the safe administration of radiotherapy.
* Pregnancy or, for women of childbearing potential, inability to use effective contraception.

• Amendola BE, Mahadevan A, Blanco Suarez JM, Griffin RJ, Wu X, Perez NC, Hippe DS, Simone CB 2nd, Mohiuddin M, Mohiuddin M, Snider JW, Zhang H, Le QT, Mayr NA. An International Consensus on the Design of Prospective Clinical-Translational Trials in Spatially Fractionated Radiation Therapy for Advanced Gynecologic Cancer. Cancers (Basel). 2022 Aug 31;14(17):4267. doi: 10.3390/cancers14174267. PMID 36077802

• Zhiyuan Xu, MD,PhD, Principal investigator, The University of Hong Kong-Shenzhen Hospital