Dose-Escalation Radiotherapy in Limited-Stage Small Cell Lung Cancer: A Phase III Randomized Trial

Official title

Phase III Randomized Clinical Trial to Evaluate the Efficacy and Safety of Twice-Daily Hyperfractionated Dose-Escalated Thoracic Radiotherapy in Patients With Limited-Stage Small Cell Lung Cancer (ESCALADOR Study)

Overview

This is a phase III clinical trial that aims to evaluate whether increasing the dose of radiotherapy given twice a day can improve treatment outcomes in patients with localized small cell lung cancer (SCLC). All patients will receive standard chemotherapy with cisplatin and etoposide and will be randomly assigned to one of three radiotherapy regimens. The main objective is to determine whether this intensified radiotherapy improves progression-free survival and overall survival. The study will also compare two different dose escalation strategies and assess treatment side effects and patients' quality of life. This research may help identify a more effective treatment approach for patients with limited-stage SCLC and could contribute to improving long-term survival in this aggressive type of cancer

Detailed description

This is a phase III, prospective, randomized, multicenter trial designed to evaluate whether a dose escalation strategy using twice-daily hyperfractionated thoracic radiotherapy can improve outcomes in patients with limited-stage small cell lung cancer (LS-SCLC).

Patients will be randomly assigned to one of three treatment arms: (A) standard-dose radiotherapy (45 Gy in 30 fractions BID), (B) escalated-dose radiotherapy (60 Gy in 40 fractions BID), or (C) standard-dose with a simultaneous integrated boost (45-54 Gy BID). All patients will receive concurrent chemotherapy with cisplatin and etoposide.

The study aims to determine if intensified radiotherapy increases progression-free survival (PFS) and overall survival (OS). Secondary objectives include comparing toxicity profiles, quality of life (using EORTC QLQ-C30 and LC13/LC29), and exploratory analyses of circulating biomarkers.

LS-SCLC has high recurrence rates despite aggressive treatment. Although BID thoracic radiotherapy (TRT) of 45 Gy is considered standard, new evidence suggests that higher doses may further improve survival without increasing toxicity. Modern radiotherapy techniques and improved imaging (e.g., PET-CT) allow more accurate targeting and potential dose escalation.

The study plans to enroll 300 patients over 36 months across 10-15 Spanish centers, coordinated by the Instituto de Investigación Biomédica de Salamanca (IBSAL) and supported by SEOR-GOECP. An interim analysis will be conducted at year 1 and year 3, with a final analysis at 5 years. Data will be collected via REDCap and follow FAIR principles. The protocol has been approved by the Salamanca Research Ethics Committee.

This trial seeks to define whether a higher radiotherapy dose improves long-term outcomes in LS-SCLC and to explore how biomarker data might inform future personalized treatments.

Interventions

• Radiation Thoracic Radiotherapy 45 Gy BID
  45 Gy delivered in 30 fractions of 1.5 Gy twice daily over three weeks, with 95% of the planning target volume (PTV) receiving at least 95% of the prescribed dose.
• Radiation Thoracic Radiotherapy 60 Gy BID
  60 Gy delivered in 40 fractions of 1.5 Gy BID. A minimum dose of 54 Gy will be accepted if organ-at-risk tolerance is exceeded.
• Radiation Thoracic Radiotherapy SIB 45-54 Gy BID
  45 Gy in 30 fractions (1.5 Gy BID) to PTV and 54 Gy in 30 fractions (1.8 Gy BID) to high-risk CTV. Both delivered simultaneously using 3D conformal planning.

Primary outcome measures

• Progression-Free Survival (PFS) [Time frame: From date of randomization until disease progression or death, whichever occurs first, assessed up to 5 years]

Secondary outcome measures (6)

• Overall Survival (OS) [Time frame: From date of randomization until death from any cause, assessed up to 5 years]
• Incidence of Acute and Late Toxicities (per CTCAE v4.0) [Time frame: From treatment initiation through 5-year follow-up]
• Quality of Life Assessment (EORTC QLQ-C30) [Time frame: Baseline, 3 months, 6 months, 12 months, and annually up to 5 years]
• Quality of life Assesment (LC13) [Time frame: Baseline, 3 months, 6 months, 12 months, and annually up to 5 years]
• Quality of Life Assesment (LC29) [Time frame: Baseline, 3 months, 6 months, 12 months, and annually up to 5 years]
• Time to First Local or Distant Recurrence [Time frame: From randomization until first documented recurrence, assessed up to 5 years]

Eligibility criteria

Inclusion criteria

• Histologically confirmed diagnosis of small cell lung cancer (SCLC)
• Limited-stage disease (Stage I-III; any T, any N, M0), eligible for definitive radiotherapy
• Measurable disease according to RECIST 1.1
• Age ≥18 years
• ECOG performance status 0-2
• No prior thoracic radiotherapy
• Signed informed consent
• Adequate hematologic function: WBC ≥3.0×10⁹/L, neutrophils ≥1.5×10⁹/L, platelets ≥100×10⁹/L, hemoglobin ≥90 g/L
• Adequate liver and renal function: total bilirubin ≤1.5×ULN, AST/ALT ≤1.5×ULN, creatinine normal or CrCl ≥60 mL/min
• Pulmonary function: FEV1 >1 L or >30% predicted; DLCO >30% predicted

Exclusion criteria

• Prior surgery or radiotherapy for any lung cancer (SCLC or NSCLC)
• Presence of malignant cells in pleural or pericardial effusion
• Serious uncontrolled systemic disorders (e.g., active infection, unstable cardiovascular disease)
• Medical, psychological, or social conditions that could interfere with compliance
• Active malignancy other than SCLC (except localized prostate/breast cancer or basal cell carcinoma)
• Refusal or inability to sign informed consent

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Spain · 13 centers

• Complejo Asistencial Universitario de Salamanca — Salamanca
• Hospital Universitario de Torrecardenas — Almería
• Hospital Universitario de Cruces — Barakaldo
• Instituto Catalán de Oncología — Girona
• Hospital Dr. Negrin — Las Palmas de Gran Canaria
• Hospital Gregorio Marañon — Madrid
• Hospital Ramon y Cajal — Madrid
• Hospital Universitario Virgen de Arrixaca — Murcia
• … and 5 more centers

Identifiers

NCT: NCT07015892 · ESCALADOR Study · PI 2024 11 1761

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗