A Randomized Trial of Standard vs. Hypofractionated Accelerated Radiotherapy for Progression in Limited-Stage Small Cell Lung Cancer (SHARP SCLC)

Standard RT using VMAT or IMRT. Accepted standard-of-care fractionation schedules include:

• 60-66 Gy in 30-33 daily fractions
• 40-45 Gy in 15 daily fractions
• 45 Gy in 30 twice-daily fractions Radiotherapy will begin as early as feasible, preferably during chemotherapy cycle 1 or 2, and no later than cycle 3.

4-6 cycles of intravenous (IV) cisplatin (75 mg/m2) or carboplatin (area under the curve of 5-6 mg/mL × min) given on day 1 or day 1-3 and etoposide (100 mg/m2) on days 1 to 3 every 3 weeks. Oral etoposide (200 mg/m²) is permitted in urgent situations and/or when IV etoposide is not feasible, at the treating clinician's discretion.

4-6 cycles of intravenous (IV) cisplatin (75 mg/m2) or carboplatin (area under the curve of 5-6 mg/mL × min) given on day 1 or day 1-3 and etoposide (100 mg/m2) on days 1 to 3 every 3 weeks. Oral etoposide (200 mg/m²) is permitted in urgent situations and/or when IV etoposide is not feasible, at the treating clinician's discretion.

Hypofractionated radiotherapy using VMAT or IMRT, prescribed to a total dose of 35 Gy in 5 fractions, with a SIB to 40 Gy for GTV where feasible. Radiotherapy will begin as early as feasible, preferably during chemotherapy cycle 1 or 2, and no later than cycle 3. Radiation will be delivered between chemotherapy cycles, ideally on days 15-20 of the respective cycle to avoid the anticipated chemotherapy nadir, and will not be administered on chemotherapy treatment days.

Progression-free survival (PFS) is defined as the time from randomization to the first occurrence of disease progression or death from any cause, whichever occurs first. Disease progression will be assessed using RECIST version 1.1 criteria. Participants without documented progression or death will be censored at the date of their last adequate disease assessment.

Changes in quality of life as reported by the participant on the Functional Assessment of Cancer Therapy: Lung (FACT-L) and EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaires

Severity and grade of side effects of treatment as reported by the physician as grade 2 or greater, using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Overall survival defined as time from randomization to death from any cause, or last follow-up, whichever occurs first

Freedom From Intrathoracic Progression defined as time from randomization to disease progression with the thorax, or last follow-up, whichever occurs first.

Freedom From Intracranial Progression defined as time from randomization to disease progression intracranially, or last follow-up, whichever occurs first.

Patient-level data on survival, disease progression, treatment-related toxicity, healthcare utilization, and health-related quality of life (EQ-5D-5L) will inform a cost-effectiveness analysis, based on modelled costs and quality-adjusted life years.