Lung Cancer, Pulmonary Complications, Radiation Fibrosis
Conditions
Keywords
radiation fibrosis, pulmonary complications, limited stage small cell lung cancer, stage II non-small cell lung cancer, stage IIIA non-small cell lung cancer, stage IIIB non-small cell lung cancer, stage I non-small cell lung cancer
Brief summary
RATIONALE: Captopril is a drug that may be able to decrease side effects caused by radiation therapy, and may improve the quality of life of patients with non-small cell lung cancer or limited-stage small cell lung cancer. PURPOSE: This randomized phase II trial is studying how well captopril works in decreasing side effects and improving the quality of life in patients who have received radiation therapy with or without chemotherapy for stage I, stage II, or stage IIIB non-small cell lung cancer or limited-stage small cell lung cancer.
Detailed description
OBJECTIVES: * Determine the effect of captopril on the incidence of pulmonary damage at 12 months after radiotherapy with or without chemotherapy in patients with stage II-IIIB non-small cell lung cancer, stage I central non-small cell lung cancer, or limited stage small cell lung cancer. * Compare the quality of life of patients treated with captopril vs patients who undergo post-radiotherapy observation only. * Determine the persistence of captopril's effect on pulmonary toxicity in these patients. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to participating center, total lung irradiated (\< 25% vs 25-37% vs more than 37%), prior surgery (yes vs no), and prior chemotherapy (yes vs no). Patients are randomized to 1 of 2 treatment arms. * Arm I: Patients receive oral captopril 3 times daily for 1 year in the absence of disease progression or unacceptable toxicity. * Arm II: Patients undergo observation only for 1 year. Quality of life is assessed at baseline and at months 3, 6, 12, and 18. Patients are followed every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 205 patients will be accrued for this study within 18 months.
Interventions
DRUGcaptopril
Captopril 12.5 mg t.i.d. for first two weeks, increased to 25 mg t.i.d. for the second two weeks of therapy. Thereafter, the dose will be increased to 50 mg t.i.d. for the remainder of the one-year of therapy (52 total weeks of drug administration).
Sponsors
National Cancer Institute (NCI)
NRG Oncology
Radiation Therapy Oncology Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * One of the following histologically or cytologically confirmed diagnoses: * Stage II-IIIB non-small cell lung cancer (NSCLC) * Stage I central NSCLC * No peripheral coin lesions * Limited stage small cell lung cancer * Nonmetastatic disease that is receiving radiotherapy and the target is confined to a single radiotherapy treatment area * Planning to receive radiotherapy * At least 45 Gy to be delivered to the target volume * More than 25% of total lung volume to receive \> 20 Gy if receiving radiotherapy alone PATIENT CHARACTERISTICS: Age * 18 and over Performance status * Zubrod 0-1 Hematopoietic * Absolute granulocyte count greater than 1,000/mm\^3 * Platelet count greater than 75,000/mm\^3 * Hemoglobin greater than 9.0 g/dL (transfusion allowed) Hepatic * Bilirubin less than 1.5 mg/dL * Serum glutamate oxaloacetate transaminase (SGOT) less than 2 times normal Renal * Blood urea nitrogen (BUN) less than 25 mg/dL * Creatinine less than 1.6 mg/dL * Urine protein less than 10 mg/dL * Urine glucose negative Cardiovascular * Systolic blood pressure greater than 110 mm Hg * Diastolic blood pressure greater than 60 mm Hg Other * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * Sodium normal * Potassium normal * No collagen vascular disease (e.g., lupus or scleroderma) * Rheumatoid arthritis allowed * No known hypersensitivity to ACE inhibitors PRIOR CONCURRENT THERAPY: Biologic therapy * Not specified Chemotherapy * Induction or concurrent chemotherapy allowed either during radiotherapy or during therapy with captopril * No concurrent methotrexate Endocrine therapy * Not specified Radiotherapy * See Disease Characteristics Surgery * Prior pulmonary lobectomy or segmentectomy allowed * No prior pneumonectomy Other * No concurrent angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists for hypertension or congestive heart failure * No concurrent lithium * No concurrent procainamide
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Therapy-induced Lung Toxicity | Once all patients have been followed for at least 12 months | Incidence of Grade 2+ radiation-induced pulmonary toxicity within 1 year after completion of radiation. Assuming that the incidence of pulmonary toxicity would be 50%, based on Fisher's exact test with a one-sided significance level of 0.05,168 randomized patients would be required to have 80% statistical power to detect a 40% relative reduction (from 50% to 30%) in the incidence of pulmonary toxicity while receiving captopril. Assuming that 15% of cases would not continue to the randomization stage and 5% of patients would be found ineligible, the target sample size was 205 patients. Given the actual sample size, power would be 25% and therefore p-values were not reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Correlation of Lung Toxicities With Biochemical Markers | Once all patients have been followed for at least 12 months | Biomarker data will not be generated from these tissue specimens, therefore this analysis will not take place. |
| Correlation of Quality of Life With Late Effects as Measured by European Organization for Research and Treatment of Cancer (EORTC) C-30 or EORTC Lung Cancer Module (LC-13) | Baseline to 18 months post treatment | Only 2 patients have the required data- only 1.2% of the planned enrollment and 2.5% of the actual enrollment- which is extremely problematic as this data cannot be generalized, leads to selection bias, and is not representative of the patient population. Therefore the analysis was not conducted. |
| Persistence of Pulmonary Toxicity at 2 Years After Completion of Study Treatment | 2 years from completion of study treatment | Patients who experienced a Grade 2+ radiation-induced pulmonary toxicity within 1 year after completion of radiation were assessed to determine if the toxicity persisted for 2 years. |
Countries
United States
Participant flow
Pre-assignment details
Patients were registered within 7 days prior to start of radiation therapy(RT) or during RT up to 48 hours prior completion of RT. They were randomized to captopril or observation within 48 hours prior to completion of RT. Eighty-one patients were registered, 48 did not continue to treatment assignment, 33 were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Observation Clinical observation | 17 |
| Captopril Captopril: 50 mg t.i.d. | 10 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 4 |
| Overall Study | Patient refusal | 0 | 2 |
Baseline characteristics
| Characteristic | Observation | Captopril | Total |
|---|---|---|---|
| Age, Continuous | 67 years | 64 years | 65 years |
| Sex: Female, Male Female | 9 Participants | 5 Participants | 14 Participants |
| Sex: Female, Male Male | 8 Participants | 5 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 17 | 8 / 10 |
| serious Total, serious adverse events | 8 / 17 | 8 / 10 |
Outcome results
Primary
Incidence of Therapy-induced Lung Toxicity
Incidence of Grade 2+ radiation-induced pulmonary toxicity within 1 year after completion of radiation. Assuming that the incidence of pulmonary toxicity would be 50%, based on Fisher's exact test with a one-sided significance level of 0.05,168 randomized patients would be required to have 80% statistical power to detect a 40% relative reduction (from 50% to 30%) in the incidence of pulmonary toxicity while receiving captopril. Assuming that 15% of cases would not continue to the randomization stage and 5% of patients would be found ineligible, the target sample size was 205 patients. Given the actual sample size, power would be 25% and therefore p-values were not reported.
Time frame: Once all patients have been followed for at least 12 months
Population: Randomized eligible patients who started study drug treatment and were followed for one year after completion of radiation treatment or experienced radiation-induced pulmonary toxicity.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Observation | Incidence of Therapy-induced Lung Toxicity | 23 percentage of participants |
| Captopril | Incidence of Therapy-induced Lung Toxicity | 14 percentage of participants |
Secondary
Correlation of Lung Toxicities With Biochemical Markers
Biomarker data will not be generated from these tissue specimens, therefore this analysis will not take place.
Time frame: Once all patients have been followed for at least 12 months
Secondary
Correlation of Quality of Life With Late Effects as Measured by European Organization for Research and Treatment of Cancer (EORTC) C-30 or EORTC Lung Cancer Module (LC-13)
Only 2 patients have the required data- only 1.2% of the planned enrollment and 2.5% of the actual enrollment- which is extremely problematic as this data cannot be generalized, leads to selection bias, and is not representative of the patient population. Therefore the analysis was not conducted.
Time frame: Baseline to 18 months post treatment
Population: Eligible patients with late effect and baseline and 12-month EORTC data
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Observation | Correlation of Quality of Life With Late Effects as Measured by European Organization for Research and Treatment of Cancer (EORTC) C-30 or EORTC Lung Cancer Module (LC-13) | NA Participants |
Secondary
Persistence of Pulmonary Toxicity at 2 Years After Completion of Study Treatment
Patients who experienced a Grade 2+ radiation-induced pulmonary toxicity within 1 year after completion of radiation were assessed to determine if the toxicity persisted for 2 years.
Time frame: 2 years from completion of study treatment
Population: Randomized patients who received study drug treatment and experienced lung toxicity at 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Observation | Persistence of Pulmonary Toxicity at 2 Years After Completion of Study Treatment | 0 Participants |
| Captopril | Persistence of Pulmonary Toxicity at 2 Years After Completion of Study Treatment | 0 Participants |