Radiation Therapy Combined With Paclitaxel and Carboplatin in Treating Patients With Stage III Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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RATIONALE: Radiation therapy uses high-energy x-rays to damage tumor cells. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug and giving them with specialized radiation therapy may kill more tumor cells. PURPOSE: This phase I/II trial is studying the effectiveness of radiation therapy combined with paclitaxel and carboplatin in treating patients who have stage III non-small cell lung cancer.

Detailed Description
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OBJECTIVES: Determine the maximum tolerated dose of 3-dimensional conformal radiotherapy when administered concurrently with paclitaxel and carboplatin in patients with inoperable stage IIIA or IIIB non-small cell lung cancer. (Phase I) (Closed to accrual as of 01/13/04.) Determine the 12-month survival rate in patients treated with this regimen. (Phase II) (Closed to accrual as of 11/27/07.) Determine the toxicity of this regimen in these patients. Determine the partial organ tolerance doses for the lung and esophagus in patients treated with this regimen. Determine the complete response rate in patients treated with this regimen. OUTLINE: This is a multicenter, dose-escalation study of 3-dimensional conformal radiotherapy. Phase I (closed to accrual as of 01/13/04): Patients undergo 3-dimensional conformal radiotherapy once daily five days a week for 7-8 weeks. Patients also receive concurrent chemotherapy comprising paclitaxel IV over 1 hour followed by carboplatin IV over 30 minutes on days 1, 8, 15, 22, 29, 36, and 43. Cohorts of 7-9 patients receive de-escalating doses of 3-dimensional conformal radiotherapy until the maximum tolerated dose (MTD) is determined when given in combination with chemotherapy. The MTD is defined as the highest dose at which no more than 1 patient experiences dose-limiting toxicity. Phase II: Additional patients are accrued and treated as above at the MTD. At least 3 weeks after completing radiotherapy, patients may receive additional chemotherapy comprising paclitaxel IV over 3 hours once and carboplatin IV over 30 minutes once. Treatment with paclitaxel and carboplatin may repeat every 3 weeks for up to 2 courses. Patients are followed every 3 months for 1 year, every 4 months for 1 year, every 6 months for 3-5 years, and then annually thereafter. PROJECTED ACCRUAL: A maximum of 73 patients (up to 27 for phase I [closed to accrual as of 10/28/04] and 46 for phase II) will be accrued for this study within 1-1.5 years.

Official Title
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A Phase I/II Dose Intensification Study Using Three Dimensional Conformal Radiation Therapy And Concurrent Chemotherapy For Patients With Inoperable, Non-Small Cell Lung Cancer

Conditions
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Lung Cancer

Intervention / Treatment
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* Drug: carboplatin
* Drug: paclitaxel
* Radiation: three-dimensional conformal radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed unresectable stage IIIB non-small cell lung cancer Squamous cell carcinoma Adenocarcinoma Large cell carcinoma Non-small cell carcinoma not otherwise specified All detectable primary tumor and involved regional lymph nodes must be encompassed by radiotherapy fields Measurable disease on 3-dimensional planning CT scan No undifferentiated small cell (oat cell or high-grade neuroendocrine) carcinoma No stage IV or recurrent disease No distant metastases or supraclavicular lymph node involvement No significant atelectasis (i.e., atelectasis of an entire lung) No pleural effusions, pericardial effusions, or superior vena cava syndrome No lung cancer within the past 2 years Ineligible for currently open Radiation Therapy Oncology Group (RTOG) phase III lung protocols PATIENT CHARACTERISTICS: Age: Not specified Performance status: Zubrod 0-1 Life expectancy: Not specified Hematopoietic: Granulocyte count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 Hepatic: Bilirubin less than 1.5 mg/dL Aspartate aminotransferase (AST) less than 2 times upper limit of normal Renal: Creatinine no greater than 2.0 mg/dL Pulmonary: Forced expiratory volume (FEV)_1 at least 1.0 L Other: Not pregnant or nursing Fertile patients must use effective contraception No weight loss greater than 5% in the past 6 months No other malignancy within the past year except nonmelanoma skin cancer Completed 3D plan with total lung V20 </= 30% mean esophageal dose </= 34 Gy and esophageal V55 </= 30% PRIOR CONCURRENT THERAPY: Biologic therapy: No prior biologic response modifiers for current lung cancer At least 5 years since prior biologic response modifiers Chemotherapy: No prior chemotherapy for current lung cancer At least 5 years since prior chemotherapy Endocrine therapy: Not specified Radiotherapy: See Disease Characteristics No prior radiotherapy to the thorax Surgery: No prior complete tumor resection
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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I: 75.25 Gy/36 fx + chemotherapy<br>Phase I: Three-dimensional conformal radiation therapy (3DRT) of 75.25 Gy given in 36 fractions (2.15 Gy per fraction) with concurrent chemotherapy consisting of weekly paclitaxel at 50mg/m2 and carboplatin at area under the curve 2mg/m2. Adjuvant systemic chemotherapy (two cycles of paclitaxel and carboplatin) following completion of RT was optional. | Drug: carboplatin<br> <br> Drug: paclitaxel<br> <br> Radiation: three-dimensional conformal radiation therapy<br> <br> |
| Experimental: Phase I: 74 Gy/37 fx + chemotherapy<br>Phase I: Three-dimensional conformal radiation therapy (3DRT) of 74 Gy given in 37 fractions (2.0 Gy per fraction) with concurrent chemotherapy consisting of weekly paclitaxel at 50mg/m2 and carboplatin at area under the curve 2mg/m2. Adjuvant systemic chemotherapy (two cycles of paclitaxel and carboplatin) following completion of RT was optional. | Drug: carboplatin<br> <br> Drug: paclitaxel<br> <br> Radiation: three-dimensional conformal radiation therapy<br> <br> |
| Experimental: Phase I: 70 Gy/35 fx + chemotherapy<br>Phase I: Three-dimensional conformal radiation therapy (3DRT) of 70 Gy given in 35 fractions (2.0 Gy per fraction) with concurrent chemotherapy consisting of weekly paclitaxel at 50mg/m2 and carboplatin at area under the curve 2mg/m2. Adjuvant systemic chemotherapy (two cycles of paclitaxel and carboplatin) following completion of RT was optional. | Drug: carboplatin<br> <br> Drug: paclitaxel<br> <br> Radiation: three-dimensional conformal radiation therapy<br> <br> |
| Experimental: Phase II: 74 Gy/37 fx + chemotherapy<br>Phase II: Three-dimensional conformal radiation therapy (3DRT) of 74 Gy given in 37 fractions (2.0 Gy per fraction) with concurrent chemotherapy consisting of weekly paclitaxel at 50mg/m2 and carboplatin at area under the curve 2mg/m2. Adjuvant systemic chemotherapy (two cycles of paclitaxel and carboplatin) following completion of RT was optional. | Drug: carboplatin<br> <br> Drug: paclitaxel<br> <br> Radiation: three-dimensional conformal radiation therapy<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of Three-dimensional Conformal Radiation Therapy (3DRT), in Terms of Gy Per Fraction, Combined With Concurrent Chemotherapy | Dose limiting toxicity (DLT) = Grade 3/4 non-hematologic toxicities (excluding nausea, vomiting, and alopecia) and Grade 4 hematologic toxicities. The DLT rate for this study was set at 40% based on Radiation Therapy Oncology Group (RTOG) study 94-10. No acute (within 90 days from start of 3DRT) DLT's in the first 5 patients (0/5) or the combination of one acute DLT in the first 5 patients (1/5) and none in the next 2 patients (0/2) was required to deem a given dose level to be acceptable. If at any time a Grade 5 toxicity (death) occurred, accrual would be suspended and the event reviewed by a study chair. At any given dose level, this design gives at least 90% confidence that the true acute DLT rate is less than 40% and the probability of not escalating when the true toxicity rate is 40% or higher is at least 83%. Rating scale: 0 = not the MTD, 1 = MTD | From start of treatment to 90 days | 
| Percentage of Patients Who Survive at Least 12 Months | Null hypothesis: p<= 62.3% (the best arm of RTOG 94-10); alternative hypothesis: p>= 77.9%. Where p is the percentage of patients alive at at 12 months. Using a one-group chi-square test with alpha = 0.10, a sample size of 50 patients provides at least 87% power to detect a 25% or greater relative increase in the 12-month survival rate, or equivalently, an absolute increase of at least 15.6 percentage points (62.3 versus 77.9). If the point estimate is greater than 71.1% (upper bound), then the conclusion is that the 12-month survival rate from the new treatment significantly improved from 62.3%. | From registration to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Highest Grade Chemotherapy/Acute RT Toxicities and Late RT Toxicities. | Highest grade toxicity per subject was counted. Toxicities were graded using the Common Toxicity Criteria (CTC) v 2.0 for chemotherapy/acute RT toxicities and using the RTOG/EORTC Late Toxicity Criteria for late RT toxicity. Grade refers to the severity of the toxicity. Both criteria assign Grades 1 through 5 with unique clinical descriptions of severity for a given toxicity based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to toxicity.Chemotherapy/Acute RT toxicities occur during chemotherapy and/or within 90 days of the start of RT. Late RT toxicities occur more than 90 days after the start of RT. | Chemotherapy/Acute RT toxicity: from start of treatment to 90 days from start of study treatment; Late RT toxicity: from 90 days after start of treatment to last follow-up (Maximum follow-up = 57.9 months.) | 
| Partial Organ Tolerance Doses for Lung and Esophagus (Percent Volume of Total Lung Receiving > 20 Gy by Toxicity Level) | Percent volume of total lung receiving > 20 Gy radiation therapy (Lung V20) was compared between the two patient groups of those who experienced a grade 3 and higher lung toxicity and those who did not. Similarly, it was also compared between the two patient groups of those who experienced a grade 2 and higher esophageal toxicity and those who did not. Toxicities graded using CTC v 2.0 for chemotherapy/acute RT toxicities and using the RTOG/EORTC Late Toxicity Criteria for late RT toxicity. Grade refers to the severity of the toxicity. Both criteria assign Grades 1 through 5 with unique clinical descriptions of severity for a given toxicity based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to toxicity. | From start of treatment to last follow-up (Maximum follow-up = 57.9 months.) | 
| Partial Organ Tolerance Doses for Lung and Esophagus (Mean Organ Dose by Toxicity Level) | Mean lung dose was compared between the two patient groups of those who experienced a grade 3 and higher lung toxicity and those who did not. Similarly, mean lung dose, and mean esophageal dose were compared between the two patient groups of those who experienced a grade 2 and higher esophageal toxicity and those who did not. Toxicities graded using CTC v 2.0 for chemotherapy/acute RT toxicities and using the RTOG/EORTC Late Toxicity Criteria for late RT toxicity. Grade refers to the severity of the toxicity. Both criteria assign Grades 1 through 5 with unique clinical descriptions of severity for a given toxicity based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to toxicity. | From start of treatment to last follow-up (Maximum follow-up = 57.9 months.) | 
| Number of Patients With Complete Response at 3 Months After Completion of Therapy | Complete response means no evidence of tumor on the CT scan. | From start of treatment until 3 months after completion of all study treatment, estimated to be 5 or 6.5 months depending whether or not subject received optional adjuvant chemotherapy. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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