Two Schedules of Hyperfractionated Thoracic Radiotherapy in Limited Disease Small Cell Lung Cancer

Study Overview
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Brief Summary
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The majority of patients with limited disease small cell lung cancer (SCLC) experience recurrent disease despite receiving concurrent chemoradiotherapy. New agents and dose-escalation of chemotherapy have not provided a survival benefit. Local failure accounts for high proportion of recurrences. Improved thoracic radiotherapy (TRT) might increase local control and thus reduce the recurrence rate and prolong survival. Positron emission tomography (PET CT) is better for staging of SCLC than computer tomography (CT) and bone scan. More precise localization of tumors leads to more accurate definition of target volumes for TRT and reduce the radiation dose to normal tissue. A large proportion of patients relapse and die within one and two year after therapy. Few patients survive longer than three years. Thus, two-year survival is considered a clinically highly relevant measure of efficacy. The aim of this study is to compare two schedules of TRT with respect to local control, progression free survival, overall survival, toxicity and health-related quality of life. In addition patients who have the best outcomes and tolerate chemoradiotherapy will be characterized (e.g. clinical characteristics, blood biomarkers, body composition).

Official Title
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A Randomized Phase II Study Comparing Two Schedules of Hyperfractionated Thoracic Radiotherapy in Limited Disease Small Cell Lung Cancer

Conditions
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Small Cell Lung Carcinoma

Intervention / Treatment
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* Radiation: 45 Gy in 30 fractions
* Radiation: 60 Gy in 40 fractions


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed small-cell lung cancer (SCLC) Limited disease (stage II-III) Stage I if ineligible for surgery Eastern Cooperative Oncology Group (ECOG) Performance 0-2 Measureable disease according to the Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 Adequate organ function defined as: (a) Serum serum alanine transaminase (ALT) ≤ 3 x upper limit of normal (ULN); (b) Total serum bilirubin ≤ 1.5 x ULN; (c) Absolute neutrophil count (ANC) ≥ 1.5 x 109/L; (d) Platelets ≥ 100 x 109/L; (e) Creatinine < 100 µmol/L and calculated creatinine-clearance > 50 ml/min. If calculated creatinine-clearance is < 50 ml/min, an ethylene diamine tetra-acetic acid (EDTA) clearance should be performed. Pulmonary function: Forced Expiratory Volume in One Second (FEV1) > 1 l or 30 % of predicted value and diffusing capacity of the lungs for carbon monoxide (DLCO) > 30 % of predicted value All fertile patients should use safe contraception Written informed consent Exclusion Criteria: prior systemic therapy for small-cell lung cancer Previous radiotherapy to the thorax malignant cells in pericardial or pleural fluid (at least one sample should be analysed if pleural fluid is present serious concomitant systemic disorders (for example active infection, unstable cardiovascular disease) that in the opinion of the investigator would compromise the patient's ability to complete the study or interfere with the evaluation of the efficacy and safety of the study treatment conditions - medical, social, psychological - which could prevent adequate information and follow-up clinically active cancer other than SCLC. Hormonal therapy for prostate cancer or breast cancer and basocellular carcinoma of the skin is allowed pregnancy, lactation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: A<br>3D conformal thoracic radiotherapy at a total dose of 45 Gy in 30 fractions, 2 fractions per day, 5 days a week | Radiation: 45 Gy in 30 fractions<br>* 3D conformal thoracic radiotherapy at a total dose of 45 Gy in 30 fractions, 2 fractions per day, 5 days a week<br>|
| Experimental: B<br>3D conformal thoracic radiotherapy at a total dose of 60 Gy in 40 fractions, 2 fractions per day, 5 days a week | Radiation: 60 Gy in 40 fractions<br>* 3D conformal thoracic radiotherapy at a total dose of 60 Gy in 40 fractions, 2 fractions per day, 5 days a week. If doses to organs at risk exceed normal tissue tolerance, the dose may be lowered to a minimum of 54 Gy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| survival | measured for all patients from the date of the first day of the first course of chemotherapy until the date of death from any cause (or last contact/observation if lost to follow-up - or the follow-up is completed before all patients die). | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| progression free survival (PFS) | measured for all patients from the date of the first day of the first course of PE to the first date of objective progression (according to RECIST 1.1) of disease or of death from any cause. For each patient who has not died or has non-progression at the cut-off date for the analysis, PFS will be censored at the date of the patient's last tumor assessment prior to the cut-off date. Statistical survival analyses will be done with Kaplan Meier. Log rank test will be used for comparing groups. | 2 years | 
| Local control | Proportion of all patients who experience disease recurrence within radiotherapy fields assessed by comparing dose plans and follow-up CT scans. | 2 years | 
| overall survival | measured for all patients from the date of the first day of the first course of chemotherapy until the date of death from any cause (or last contact/observation if lost to follow-up - or the follow-up is completed before all patients die). | 3 years | 
| toxicity | assessed for all patients receiving at least one course of chemotherapy from reported blood values and adverse event. Classified and graded according to CTCAE 4.0. Compared using Pearson's Chi-square and Fischer's exact tests. | 2 years | 
| health related quality of life (HRQoL) | assessed from completed questionnaires. Patients will report HRQoL on the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) C30 and the lung cancer specific module LC13. The QLQ-C30 measures fundamental aspects of HRQoL and symptoms commonly reported by cancer patients in general, the LC13 measures symptoms commonly associated with lung cancer and its treatment. All HRQoL scores will be transformed to a scale from 0 to 100 according to the EORTC scoring manual. A difference in mean scores of >10 is considered clinically relevant. For group comparisons of baseline scores during and after chemotherapy, and changes in scores from baseline, the Mann-Whitney test will be used. Primary HRQoL-endpoints are dysphagia and dyspnea. | From baseline, before and after radiotherapy and then at follow-up every 3 months until 24 months after start of chemotherapy. Then every 6 months until 5 year after start of therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Radiotherapy, Radiotherapy dosage, Dose fractionation, Radiotherapy, image-guided, Thorax