Lung Cancer
Conditions
Keywords
squamous cell lung cancer, large cell lung cancer, stage IIIA non-small cell lung cancer, stage IIIB non-small cell lung cancer, adenocarcinoma of the lung, adenosquamous cell lung cancer, bronchoalveolar cell lung cancer
Brief summary
This randomized phase III trial is studying carboplatin, paclitaxel, radiation therapy, and thalidomide to see how well they work compared to carboplatin, paclitaxel, and radiation therapy alone in treating patients with newly diagnosed stage III non-small cell lung cancer. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Thalidomide may stop the growth of non-small cell lung cancer by stopping blood flow to the tumor. It is not yet known if combination chemotherapy plus radiation therapy is more effective with or without thalidomide.
Detailed description
OBJECTIVES: I. Compare the survival and time to progression of patients with stage IIIA or IIIB non-small cell lung cancer when treated with carboplatin, paclitaxel, and chemoradiotherapy with or without thalidomide. II. Evaluate the toxicity of the thalidomide-containing regimen and compare response rates of the two groups. III. Determine whether the inactivation of p16, Death-associated protein kinase (DAP-kinase), O6-methylguanine-DNA methyltransferase (MGMT) gene, or tissue-inhibitor of metalloproteinase 3 (TIMP-3) genes can be used to predict survival in these patients treated with this regimen. IV. Determine whether the detection of a methylation biomarker in serum can be used to predict survival in these patients treated with this regimen. OUTLINE: This is a randomized study. Patients are stratified according to disease histology (squamous vs nonsquamous), performance status (0 vs 1), disease stage (IIIA vs IIIB), and time of randomization (before addition of chemoradiotherapy vs after). Patients are randomized to one of two treatment arms. ARM A: Patients receive paclitaxel intravenously (IV) over 3 hours immediately followed by carboplatin IV over 15-30 minutes on days 1 and 22. Treatment continues every 22 days in the absence of unacceptable toxicity or disease progression. ARM B: Patients receive paclitaxel and carboplatin as in arm A. Patients also receive oral thalidomide and oral low-dose aspirin daily beginning on day 1 for up to 24 months in the absence of disease progression. Beginning between days 43-50, patients in both arms with stable or responding disease receive chemoradiotherapy comprising paclitaxel IV over 1 hour and carboplatin IV over 15-30 minutes once weekly for 6 weeks and radiotherapy (RT) 5 days a week for 6 weeks. Arm B patients continue oral thalidomide. Patients are followed every 2 months for 2 years and then every 6 months for 3 years.
Interventions
DRUGcarboplatin
Induction Chemotherapy dosing: AUC=6.0, 15-30 min IV infusion immediately following paclitaxel, Day 1 and Day 22. Concurrent Chemotherapy / Radiotherapy dosing, AUC=2; 15- 30 minutes IV infusion immediately following paclitaxel; administered weekly during radiotherapy
DRUGpaclitaxel
Induction chemotherapy dosing: 225 mg/m² (3 hour infusion) Day 1 and Day 22. Concurrent Chemotherapy / Radiotherapy dosing: 45 mg/m2; administered weekly during radiotherapy over one hour
DRUGthalidomide
Induction Chemotherapy dosing: oral daily, starting Day 1 for 24 months or until disease progression. Concurrent Chemotherapy / Radiotherapy dosing: oral daily, begin with 200 mg thalidomide as a single dose at bedtime. The dose is then increased by 100 mg every week as tolerated up to a total dose of 1000 mg.
RADIATIONradiation therapy
Radiation therapy started between days 43-50 from day 1 of cycle 1. The primary tumor and areas of known nodal disease received 60 Gy at 2.0 Gy fractions, 5 fractions/week for 30 fractions over 6 weeks to the post chemotherapy tumor volume as seen on computed tomography (CT). The initial 50 Gy was delivered to target volume (TV). The final 10 Gy was delivered to a reduced volume targeting defined by TV
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed newly diagnosed non-small cell bronchogenic carcinoma * Squamous cell * Adenocarcinoma * Large cell undifferentiated * Bronchoalveolar * Non-small cell carcinoma not otherwise stated * Unresectable stage IIIA * Mediastinal lymph node enlargement of at least 1 cm but less than 2 cm on computed tomography (CT) scans must have mediastinotomy or thoracoscopy to rule out resectability OR * Stage IIIB disease without significant pleural effusion * Seen on CT scan only (not seen on chest x-ray) or does not reaccumulate after 1 thoracentesis and is cytologically negative * Metastases to contralateral, mediastinal, or supraclavicular nodes allowed * Bidimensionally measurable or evaluable disease * 18 and over * ECOG performance status 0-1 * Adequate hematopoietic, hepatic, and renal function obtained \<=4 weeks prior to registration: * Platelet count at least 100,000/mm\^3 * White Blood Cell (WBC) count at least 4,000/mm\^3 OR absolute neutrophil count at least 2,000/mm\^3 * Bilirubin normal * Serum glutamic oxaloacetic transaminase (SGOT) no greater than 2.5 times upper limit of normal * Creatinine no greater than 1.5 mg/dL OR creatinine clearance at least 60 mL/min * Fertile patients must use 2 methods of effective contraception for 4 weeks prior to, during, and for 4 weeks after study therapy * Concurrent filgrastim (G-CSF) allowed for persistent neutropenia
Exclusion criteria
* Positive pregnancy test,pregnant or nursing * Uncontrolled high blood pressure, unstable angina, congestive heart failure, or myocardial infarction within the prior year * Serious cardiac arrhythmias requiring medication * Prior radiotherapy to only area of measurable or active tumor * Less than 5 years since prior chemotherapy * Other active malignancies * Serious uncontrolled active infection * Evidence of greater than grade 1 neuropathy by history or physical examination * History of seizure disorders * Contraindication to daily low-dose (81 mg/day) aspirin
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival Time | every other month until 24 months from study entry, then every 3 months for year 3, every 4 months for year 4 and every 6 months for year 5 | Survival time is defined as time from study entry to death from any cause |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Disease Progression | every other month until 24 months from study entry, every 3 months for year 3, every 4 months for the 4th year and every 6 months for the 5th year | Time to disease progression is defined as the time from randomization to documented disease progression or to death without progression. Patients without documented progression or death reported were censored at the time of the last documented disease evaluation. Progression is defined, using the Response Evaluation Criteria In Solid Tumors (RECIST), as a measurable increase in the smallest dimension of any target or non-target lesion, or the appearance of new lesions, since baseline. |
| Response Rate at Best Response to Treatment | every other month until 24 months from study entry, every 3 months for year 3, every 4 months for the 4th year and every 6 months for the 5th year | Proportion of patients with complete or partial response using the Response Evaluation Criteria In Solid Tumors (RECIST) v1.0. Complete response is defined as the complete disappearance of all clinically detectable malignant disease for at least 4 weeks. Partial response is defined as greater than or equal to 50% decrease in tumor size for at least 4 weeks without increase in size of any area of known malignant disease of greater than 25%, or appearance of new areas of malignant disease. |
Countries
South Africa, United States
Participant flow
Recruitment details
The study was activated on January 27, 2000, and was terminated on October 26, 2006. 589 patients were enrolled to the study.
Participants by arm
| Arm | Count |
|---|---|
| Arm A (Paclitaxel + Carboplatin + Radiation ) Active comparator. Induction dosing: Paclitaxel, 225 mg/m²; Carboplatin, AUC=6.0. Concurrent dosing: Paclitaxel, 45 mg/m2; Carboplatin: AUC=2. | 275 |
| Arm B (Paclitaxel + Carboplatin + Radiation + Thalidomide) Experimental arm. Thalidomide: daily, patients begin with 200 mg thalidomide PO as a single dose at bedtime. The dose is then increased by 100 mg every week as tolerated up to a total dose of 1000 mg; low dose aspirin: 81mg PO daily.
Paclitaxel, carboplatin and radiation same as active comparator. | 271 |
| Total | 546 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 31 | 93 |
| Overall Study | Death | 5 | 5 |
| Overall Study | error | 3 | 1 |
| Overall Study | Lack of Efficacy | 43 | 113 |
| Overall Study | missing data | 14 | 11 |
| Overall Study | Other | 13 | 21 |
| Overall Study | other disease | 0 | 3 |
| Overall Study | Protocol Violation | 2 | 2 |
| Overall Study | Withdrawal by Subject | 7 | 33 |
Baseline characteristics
| Characteristic | Arm A (Paclitaxel + Carboplatin + Radiation ) | Arm B (Paclitaxel + Carboplatin + Radiation + Thalidomide) | Total |
|---|---|---|---|
| Age, Continuous | 62.9 years STANDARD_DEVIATION 9 | 62.2 years STANDARD_DEVIATION 10.5 | 62.6 years STANDARD_DEVIATION 9.8 |
| Sex: Female, Male Female | 104 Participants | 108 Participants | 212 Participants |
| Sex: Female, Male Male | 171 Participants | 163 Participants | 334 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 283 / 289 | 284 / 288 |
| serious Total, serious adverse events | 222 / 289 | 249 / 288 |
Outcome results
Primary
Overall Survival Time
Survival time is defined as time from study entry to death from any cause
Time frame: every other month until 24 months from study entry, then every 3 months for year 3, every 4 months for year 4 and every 6 months for year 5
Population: intent to treat analysis in the 546 eligible patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Paclitaxel + Carboplatin + Radiation ) | Overall Survival Time | 15.3 Months |
| Arm B (Paclitaxel + Carboplatin + Radiation + Thalidomide) | Overall Survival Time | 16.0 Months |
p-value: 0.99Log Rank
Secondary
Response Rate at Best Response to Treatment
Proportion of patients with complete or partial response using the Response Evaluation Criteria In Solid Tumors (RECIST) v1.0. Complete response is defined as the complete disappearance of all clinically detectable malignant disease for at least 4 weeks. Partial response is defined as greater than or equal to 50% decrease in tumor size for at least 4 weeks without increase in size of any area of known malignant disease of greater than 25%, or appearance of new areas of malignant disease.
Time frame: every other month until 24 months from study entry, every 3 months for year 3, every 4 months for the 4th year and every 6 months for the 5th year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Paclitaxel + Carboplatin + Radiation ) | Response Rate at Best Response to Treatment | 0.35 Proportion of participants |
| Arm B (Paclitaxel + Carboplatin + Radiation + Thalidomide) | Response Rate at Best Response to Treatment | 0.38 Proportion of participants |
Secondary
Time to Disease Progression
Time to disease progression is defined as the time from randomization to documented disease progression or to death without progression. Patients without documented progression or death reported were censored at the time of the last documented disease evaluation. Progression is defined, using the Response Evaluation Criteria In Solid Tumors (RECIST), as a measurable increase in the smallest dimension of any target or non-target lesion, or the appearance of new lesions, since baseline.
Time frame: every other month until 24 months from study entry, every 3 months for year 3, every 4 months for the 4th year and every 6 months for the 5th year
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Paclitaxel + Carboplatin + Radiation ) | Time to Disease Progression | 7.4 Months |
| Arm B (Paclitaxel + Carboplatin + Radiation + Thalidomide) | Time to Disease Progression | 7.8 Months |