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High-Dose or Standard-Dose Radiation Therapy and Chemotherapy With or Without Cetuximab in Treating Patients With Newly Diagnosed Stage III Non-Small Cell Lung Cancer That Cannot Be Removed by Surgery

Primary Purpose

Lung Cancer, Radiation Toxicity

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Cetuximab

Carboplatin

Paclitaxel

60 Gy RT

74 Gy RT

About this trial

This is an interventional treatment trial for Lung Cancer focused on measuring radiation toxicity, stage IIIA non-small cell lung cancer, stage IIIB non-small cell lung cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria:

Pathologically proven (either histologic or cytologic) diagnosis of Stage IIIA or IIIB non-small cell lung cancer (NSCLC); excluding patients with N3 disease based on supraclavicular or contralateral hilar adenopathy, [according to American Joint Committee on Cancer (AJCC) Staging, 6th edition; see appendix III] within 12 weeks of registration; patients who present with N2 or N3 disease and an undetectable NSCLC primary tumor also are eligible.
Patients must be considered unresectable or inoperable; Note: Patients who have had a nodal recurrence after surgery for an early-stage NSCLC are eligible if the following criteria are met:
- Nodal recurrence must be N1 or N2; N3 is not eligible.
- The initial primary must have been staged as T1-2, N0, M0.
- The node must be biopsied within 12 weeks of registration.
- The node must be measurable.
- The patient must not have received prior chemotherapy or radiation for this lung cancer.
- Prior curative surgery must have been at least 6 months prior to the nodal recurrence.
- The exception to a prior invasive malignancy does not apply to the initial lung primary.
Stage III A or B disease, including no distant metastases, based upon the following minimum diagnostic workup are acceptable:
- History/physical examination, including documentation of height, weight, body surface area (BSA), and vital signs within 8 weeks prior to registration;
- Computed tomographic (CT)/Magnetic Resonance Imaging (MRI) imaging of the lung and upper abdomen through the adrenal glands within 6 weeks prior to registration;
- An MRI of the brain with contrast (or CT with contrast if MRI is medically contraindicated) within 6 weeks prior to registration; Note: The use of intravenous contrast is required for the MRI or CT. An MRI without contrast is only permitted if the patient has a contrast allergy.
- Whole-body fluorodeoxyglucose (FDG) - Positron Emission Tomography(PET) or PET/CT or if no PET is available, a bone scan is required within 6 weeks prior to registration; Note: If a PET is done that shows clear adrenals and lungs, then a CT scan of chest only is permitted.
If a pleural effusion is present, the following criteria must be met to exclude malignant involvement (incurable T4 disease):
- When pleural fluid is visible on both the CT scan and on a chest x-ray, a pleuracentesis is required to confirm that the pleural fluid is cytologically negative.
- Exudative pleural effusions are excluded, regardless of cytology;
- Effusions that are minimal (i.e. not visible on chest x-ray) that are too small to safely tap are eligible.
Patients must have measurable or evaluable disease.
Patients with post-obstructive pneumonia are eligible.
Patients must be at least 3 weeks from prior thoracotomy (if performed).
Zubrod Performance Status 0-1;
Age ≥ 18;
Pulmonary function tests (PFTs) including forced expiratory volume in one second (FEV1) within 12 weeks prior to registration; for FEV1, the best value obtained pre- or post bronchodilator must be ≥ 1.2 liters/second or ≥ 50% predicted.
Complete blood count (CBC)/differential obtained within 2 weeks prior to registration on study, with adequate bone marrow function defined as follows:
- Absolute neutrophil count (ANC) ≥ 1,800 cells/mm3;
- Platelets ≥ 100,000 cells/mm3;
- Hemoglobin ≥ 10.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 10.0 g/dl is acceptable.)
Serum creatinine within normal institutional limits or creatinine clearance ≥60 ml/min;
Bilirubin must be within or below normal institutional limits;
Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) < 2.5 x the institutional upper limit of normal (IULN);
Patient must sign study specific informed consent prior to study entry.

Exclusion Criteria:

N3 supraclavicular disease;
Greater than minimal, exudative, or cytologically positive pleural effusions;
Involved contralateral hilar nodes (i.e. greater than 1.5 cm on short axis or positive on PET scan);
≥ 10% weight loss within the past month;
Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years; non-invasive conditions such as carcinoma in situ of the breast, oral cavity, or cervix are all permissible.
Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable.
Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields;
Prior therapy that specifically and directly targets the epidermal growth factor receptor (EGFR) pathway;
Prior severe infusion reaction to a monoclonal antibody;
Severe, active co-morbidity, defined as follows:
- Significant history of uncontrolled cardiac disease; i.e., uncontrolled hypertension, unstable angina, myocardial infarction within the last 6 months, uncontrolled congestive heart failure, and cardiomyopathy with decreased ejection fraction.
- Transmural myocardial infarction within the last 6 months;
- Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration;
- Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before registration;
- Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects;
- Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive. Protocol-specific requirements may also exclude immuno-compromised patients.
Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.
Any history of allergic reaction to paclitaxel or other taxanes, or to carboplatin;
Uncontrolled neuropathy grade 2 or greater regardless of cause.

Sites / Locations

UAB Comprehensive Cancer Center
Mayo Clinic Scottsdale
Arizona Oncology - Tucson
Mercy Cancer Center at Mercy San Juan Medical Center
Enloe Cancer Center at Enloe Medical Center
Cancer Care Center at John Muir Health - Concord Campus
Saint Agnes Cancer Center at Saint Agnes Medical Center
Rebecca and John Moores UCSD Cancer Center
Memorial Medical Center
St. Joseph Hospital Regional Cancer Center - Orange
Feather River Hospital Cancer Center
Radiation Oncology Center - Roseville
Radiological Associates of Sacramento Medical Group, Incorporated
University of California Davis Cancer Center
Saint Helena Hospital
UCSF Helen Diller Family Comprehensive Cancer Center
Stanford Cancer Center
Penrose Cancer Center at Penrose Hospital
Swedish Medical Center
Poudre Valley Radiation Oncology
North Suburban Medical Center
CCOP - Christiana Care Health Services
Washington Cancer Institute at Washington Hospital Center
Broward General Medical Center Cancer Center
University of Florida Shands Cancer Center
Memorial Cancer Institute at Memorial Regional Hospital
Integrated Community Oncology Network
Baptist Cancer Institute - Jacksonville
Integrated Community Oncology Network at Southside Cancer Center
Mayo Clinic - Jacksonville
Baptist Medical Center South
Ella Milbank Foshay Cancer Center at Jupiter Medical Center
CCOP - Mount Sinai Medical Center
Baptist-South Miami Regional Cancer Program
Integrated Community Oncology Network - Orange Park
M.D. Anderson Cancer Center at Orlando
Florida Cancer Center - Palatka
Sacred Heart Cancer Center at Sacred Heart Hospital
Flagler Cancer Center
Georgia Cancer Center for Excellence at Grady Memorial Hospital
Emory Crawford Long Hospital
Piedmont Hospital
Winship Cancer Institute of Emory University
Charles B. Eberhart Cancer Center at DeKalb Medical Center
Saint Alphonsus Cancer Care Center at Saint Alphonsus Regional Medical Center
Mountain States Tumor Institute at St. Luke's Regional Medical Center
University of Chicago Cancer Research Center
Creticos Cancer Center at Advocate Illinois Masonic Medical Center
Community Cancer Center
Cancer Treatment Center at Pekin Hospital
Methodist Medical Center of Illinois
OSF St. Francis Medical Center
Radiation Oncology Associates Southwest
Parkview Regional Cancer Center at Parkview Health
Center for Cancer Care at Goshen General Hospital
Central Indiana Cancer Centers - East
Community Regional Cancer Care at Community Hospital East
Community Regional Cancer Care at Community Hospital North
Cancer Center at Ball Memorial Hospital
Mercy Regional Cancer Center at Mercy Medical Center
John Stoddard Cancer Center at Iowa Methodist Medical Center
Mercy Cancer Center at Mercy Medical Center - Des Moines
Mercy Cancer Center at Mercy Medical Center - North Iowa
Siouxland Hematology-Oncology Associates, LLP
Central Baptist Hospital
Tulane Cancer Center Office of Clinical Research
Mary Bird Perkins Cancer Center - Baton Rouge
MBCCOP - LSU Health Sciences Center
CCOP - Ochsner
Greenebaum Cancer Center at University of Maryland Medical Center
St. Agnes Hospital Cancer Center
Shore Regional Cancer Center at Memorial Hospital - Easton
Peninsula Regional Medical Center
Baystate Regional Cancer Program at D'Amour Center for Cancer Care
Saint Joseph Mercy Cancer Center
Barbara Ann Karmanos Cancer Institute
Josephine Ford Cancer Center at Henry Ford Hospital
Lacks Cancer Center at Saint Mary's Health Care
Van Elslander Cancer Center at St. John Hospital and Medical Center
West Michigan Cancer Center
St. Mary Mercy Hospital
Mercy Regional Cancer Center at Mercy Hospital
Fairview Ridges Hospital
Minnesota Oncology Hematology, PA - Maplewood
Virginia Piper Cancer Institute at Abbott - Northwestern Hospital
Humphrey Cancer Center at North Memorial Outpatient Center
Mayo Clinic Cancer Center
CentraCare Clinic - River Campus
Regions Hospital Cancer Care Center
University of Mississippi Cancer Clinic
Regional Cancer Center at Singing River Hospital
Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
Barnes-Jewish West County Hospital
Siteman Cancer Center at Barnes-Jewish St. Peters Hospital - St. Peters
Billings Clinic - Downtown
Good Samaritan Cancer Center at Good Samaritan Hospital
Saint Elizabeth Cancer Institute at Saint Elizabeth Regional Medical Center
Methodist Estabrook Cancer Center
CCOP - Nevada Cancer Research Foundation
Renown Institute for Cancer at Renown Regional Medical Center
Saint Mary's Regional Medical Center
Payson Center for Cancer Care at Concord Hospital
Center for Cancer Care at Exeter Hospital
Elliot Regional Cancer Center at Elliot Hospital
Fox Chase Virtua Health Cancer Program at Virtua Memorial Hospital Marlton
UMDNJ University Hospital
J. Phillip Citta Regional Cancer Center at Community Medical Center
Cancer Institute of New Jersey at Cooper - Voorhees
University of New Mexico Cancer Center
New York Oncology Hematology, PC at Albany Regional Cancer Care
Veterans Affairs Medical Center - Albany
Sands Cancer Center
St. Luke's - Roosevelt Hospital Center - St.Luke's Division
Highland Hospital of Rochester
University Radiation Oncology at Parkridge Hospital
James P. Wilmot Cancer Center at University of Rochester Medical Center
SUNY Upstate Medical University Hospital
Alamance Cancer Center at Alamance Regional Medical Center
Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
Blumenthal Cancer Center at Carolinas Medical Center
Presbyterian Cancer Center at Presbyterian Hospital
Kinston Medical Specialists
FirstHealth Moore Regional Community Hospital Comprehensive Cancer Center
Cancer Centers of North Carolina - Raleigh
CCOP - MeritCare Hospital
Altru Cancer Center at Altru Hospital
Trinity CancerCare Center
McDowell Cancer Center at Akron General Medical Center
Summa Center for Cancer Care at Akron City Hospital
Barberton Citizens Hospital
Aultman Cancer Center at Aultman Hospital
Adena Regional Medical Center
Charles M. Barrett Cancer Center at University Hospital
Case Comprehensive Cancer Center
Cleveland Clinic Cancer Center at Fairview Hospital
Cleveland Clinic Taussig Cancer Center
Riverside Methodist Hospital Cancer Care
Cleveland Clinic Cancer Center
Hillcrest Cancer Center at Hillcrest Hospital
Southwest General Health Center
UHHS Chagrin Highlands Medical Center
St. Charles Mercy Hospital
North Coast Cancer Care, Incorporated
Flower Hospital Cancer Center
St. Anne Mercy Hospital
UHHS Westlake Medical Center
Cleveland Clinic - Wooster
Oklahoma University Cancer Institute
Natalie Warren Bryant Cancer Center at St. Francis Hospital
Willamette Valley Cancer Center - Eugene
Morgan Cancer Center at Lehigh Valley Hospital - Cedar Crest
Bryn Mawr Hospital
Geisinger Cancer Institute at Geisinger Health
Northeast Radiation Oncology Center
Dale and Frances Hughes Cancer Center at Pocono Medical Center
Regional Cancer Center - Erie
Penn State Hershey Cancer Institute at Milton S. Hershey Medical Center
Cancer Center of Paoli Memorial Hospital
Kimmel Cancer Center at Thomas Jefferson University - Philadelphia
Fox Chase Cancer Center - Philadelphia
Frankford Hospital Cancer Center - Torresdale Campus
Albert Einstein Cancer Center
McGlinn Family Regional Cancer Center at Reading Hospital and Medical Center
Frank M. and Dorothea Henry Cancer Center at Geisinger Wyoming Valley Medical Center
Lankenau Cancer Center at Lankenau Hospital
Hollings Cancer Center at Medical University of South Carolina
Cancer Centers of the Carolinas - Faris Road
CCOP - Greenville
Cancer Centers of the Carolinas - Seneca
Gibbs Regional Cancer Center at Spartanburg Regional Medical Center
Sanford Cancer Center at Sanford USD Medical Center
Christine LaGuardia Phillips Cancer Center at Wellmont Holston Valley Medical Center
Harrington Cancer Center
Texas Oncology, PA at Texas Cancer Center - Arlington South
Texas Oncology, PA at Harris Center HEB
Texas Oncology, PA at Texas Cancer Center - Denton South
Klabzuba Cancer Center at Harris Methodist Fort Worth Hospital
M. D. Anderson Cancer Center at University of Texas
Longview Cancer Center
West Texas Cancer Center
Cancer Care Centers of South Texas - Northeast
Texas Oncology, PA at Texas Cancer Center - Sherman
Texas Oncology, PA at Texas Oncology Cancer Center Sugar Land
Tyler Cancer Center
Jon and Karen Huntsman Cancer Center at Intermountain Medical Center
Utah Valley Regional Medical Center - Provo
Dixie Regional Medical Center - East Campus
Utah Cancer Specialists at UCS Cancer Center
Fletcher Allen Health Care - University Health Center Campus
University of Virginia Cancer Center
CCOP - Virginia Mason Research Center
Cancer Care Northwest - Spokane South
Theda Care Cancer Institute
Midelfort Clinic - Luther
Luther Midlelfort Hospital
Bellin Memorial Hospital
St. Mary's Hospital Medical Center - Green Bay
St. Vincent Hospital Regional Cancer Center
Gundersen Lutheran Center for Cancer and Blood
Bay Area Cancer Care Center at Bay Area Medical Center
Medical College of Wisconsin Cancer Center
Veterans Affairs Medical Center - Milwaukee
D.N. Greenwald Center
All Saints Cancer Center at Wheaton Franciscan Healthcare
Door County Cancer Center at Door County Memorial Hospital
Waukesha Memorial Hospital Regional Cancer Center
Riverview UW Cancer Center at Riverview Hospital
Tom Baker Cancer Centre - Calgary
CancerCare Manitoba
Princess Margaret Hospital
Hopital Notre-Dame du CHUM
Allan Blair Cancer Centre at Pasqua Hospital
Saskatoon Cancer Centre at the University of Saskatchewan

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Experimental

Arm Label

60 Gy RT

74 Gy RT

60 Gy RT + Cetuximab

74 Gy RT + Cetuximab

Arm Description

60 Gy Radiation therapy with concurrent paclitaxel and carboplatin followed by consolidation paclitaxel and carboplatin

74 Gy Radiation therapy with concurrent paclitaxel and carboplatin followed by consolidation paclitaxel and carboplatin

60 Gy Radiation therapy with concurrent cetuximab, paclitaxel, and carboplatin followed by consolidation cetuximab, paclitaxel, and carboplatin

74 Gy Radiation therapy with concurrent cetuximab, paclitaxel, and carboplatin followed by consolidation cetuximab, paclitaxel, and carboplatin

Outcomes

Primary Outcome Measures

Overall Survival

Survival time is defined as time from randomization to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact.

Secondary Outcome Measures

Progression-free Survival

A failure for progression-free survival (PFS) is the first occurrence of local or regional progression, distant metastases, or death from any cause. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a nontarget lesion, or the appearance of new lesions. Time is measured from the date of randomization to the date of first failure. Patients without failure are censored at the date of last follow-up.

Local-regional Failure (Reported as Two-year Estimates)

A failure for local-regional failure is the first occurrence of local or regional progression. Time is measured from the date of randomization to the date of first failure. Patients alive without local or regional failure at the time of last follow-up are censored. Patients who died without local or regional failure are considered as having competing risk at the time of death. Local-regional failure was estimated by the cumulative incidence method and 2 year estimates are reported.

Percentage of Participants With Grade 3-5 Esophagitis and Pneumonitis Adverse Events as Assessed by NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v3.0

Treatment-related esophagitis and pneumonitis were assessed graded using the CTCAE v3.0. Comparisons are only made between radiation therapy dosing levels because the cetuximab regimen was known to be safe in combination with radiation therapy.

Percentage of Participants With Other Grade 3-5 Adverse Events as Assessed by NCI CTCAE v3.0

Treatment-related adverse events other than esophagitis and pneumonitis were assessed graded using the CTCAE v3.0. Comparisons are only made between radiation therapy dosing levels because the cetuximab regimen was known to be safe in combination with radiation therapy.

Death During or Within 30 Days of Discontinuation of Protocol Treatment

Deaths regardless of cause and occuring during or within 30 days of discontinuation of protocol treatment were evaluated.

Percentage of Patients With Decline From Baseline to 3 Months in the Lung Cancer Subscale (LCS) of the Functional Assessment of the Cancer Therapy Trial Outcome Index (FACT-TOI).

A decline of 2 points in the LCS from baseline to 3 months was considered a clinically meaningful change indicating a decline in quality of life. Comparisons are only made between radiation therapy dosing levels because the cetuximab regimen was known to be safe in combination with radiation therapy.

Patient-reported Swallowing Score (Area Under the Curve)

Patients completed a swallowing diary prior to the start of treatment and then daily during treatment. Patients recorded a score to indicate problems with swallowing on that day (1-None, 2-Mild soreness only, 3-Can swallow solids with some difficulty, 4-Cannot swallow solids, 5-Cannot swallow liquids). These scores were then plotted across time and the area under the curve from baseline until the end of week 6 was calculated. A lower area under the curve indicates better swallowing ability. Comparisons are only made between radiation therapy dosing levels because the cetuximab regimen was known to be safe in combination with radiation therapy.

EuroQoL (EQ5D) Visual Analog Scale (VAS) Through One Year (Area Under the Curve)

The visual analogue scale is a self-assessment of current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The area under the curve of each subject's EQ5D visual analog scale (VAS) response trajectory within 1 year was calculated. The EQ5D VAS utility was normalized by the baseline score. The trajectory included all available time points through one year. If a subject died within one year, the EQ5D VAS was reduced to 0 at the time of death. If subject was censored within one year, the EQ5D utility curve was truncated at the time of censoring. The scores were plotted across time and the area under the curve was calculated. A greater area under the curve indicates a better health state. Comparisons are only made between radiation therapy dosing levels because the cetuximab regimen was known to be safe in combination with radiation

Overall Survival and Local-regional Failure by Epithelial Growth Factor Receptor (EGFR) Group

EGFR is a protein that is present on the surface of both normal cells and cancer cancer cells. EGFR H-Score is a measure of staining intensity ranging from 0 to 300 where a higher value indicates greater intensity of EGFR. Available tumor samples were evaluated for EGFR and given an H-Score. Patients were divided into two groups based on H-Score values dichotomized at 200. All event times are time from randomization to date of event or censoring. A survival event is death from any cause, patients without events are censored at the date of last contact, and survival rates are estimated by Kaplan-Meier method. A local-regional event is the first development of progressive disease locally or regionally, patients who do not have an event are censored at the date of death or last contact, and event rates are estimated by cumulative incidence. Two-year rates are reported.

Percentage of Patients With Grade 3+ Adverse Events by Epithelial Growth Factor Receptor (EGFR) Group

EGFR is a protein that is present on the surface of both normal cells and cancer cancer cells. EGFR H-Score is a measure of staining intensity ranging from 0 to 300 where a higher value indicates greater intensity of EGFR. Available tumor samples were evaluated for EGFR and given an H-Score. Patients were divided into two groups based on H-Score values dichotomized at 200. Worst toxicity as determined by adverse events was used as a measure of a patient's quality of life (QOL). Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE 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 AE. Highest grade (worst) adverse event (AE) per subject was counted.

Prognostic and Predictive Effects of Gross Tumor Volume (GTV) on Overall Survival

Gross tumor volume (GTV) is defined as the combined volume (cubic centimeters) of the primary tumor and clinically positive lymph nodes seen either on the planning computed tomography (CT) scan or the pretreatment positron emission tomography (PET) scan. Survival time is defined as time from randomization to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. GTV was evaluated as a continuous variable therefore overall survival time is not summarized by GTV. "Prognostic" refers to the main effect and "predictive" refers to the interaction between GTV and treatment arm.

Prognostic Value of Pre-treatment Standardized Uptake Value (SUV) of Positron Emission Tomography (PET) Scan in Predicting Survival, Distant Metastasis, and Local-regional Failure

Standardized uptake value (SUV) is a simple way of determining activity in PET imaging. It is a mathematically derived ratio of tissue radioactivity concentration at a point in time and the injected dose of radioactivity per kilogram of the patient's body weight. All event times are time from randomization to date of event or censoring. A survival event is death from any cause, patients without events are censored at the date of last contact, and survival rates are estimated by Kaplan-Meier method. Local-regional and distant metastasis events are the first development of progressive disease locally/regionally or distant metastasis, respectively, patients who do not have an event are censored at the date of death or last contact, and event rates are estimated by cumulative incidence. Two-year rates are presented. PET SUV was evaluated as a continuous variable therefore the outcome variables are not summarized by PET SUV.

Full Information

NCT ID

NCT00533949

First Posted

September 20, 2007

Last Updated

May 23, 2022

Sponsor

Radiation Therapy Oncology Group

Collaborators

National Cancer Institute (NCI), North Central Cancer Treatment Group, Cancer and Leukemia Group B, NRG Oncology

1. Study Identification

Unique Protocol Identification Number

NCT00533949

Brief Title

High-Dose or Standard-Dose Radiation Therapy and Chemotherapy With or Without Cetuximab in Treating Patients With Newly Diagnosed Stage III Non-Small Cell Lung Cancer That Cannot Be Removed by Surgery

Official Title

A Randomized Phase III Comparison of Standard-Dose (60 Gy) Versus High-Dose (74 Gy) Conformal Radiotherapy With Concurrent and Consolidation Carboplatin/Paclitaxel +/- Cetuximab (IND #103444) in Patients With Stage IIIA/IIIB Non-Small Cell Lung Cancer

Study Type

Interventional

2. Study Status

Record Verification Date

May 2022

Overall Recruitment Status

Completed

Study Start Date

November 2007 (undefined)

Primary Completion Date

June 2013 (Actual)

Study Completion Date

May 20, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Radiation Therapy Oncology Group

Collaborators

National Cancer Institute (NCI), North Central Cancer Treatment Group, Cancer and Leukemia Group B, NRG Oncology

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as paclitaxel, carboplatin work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether high-dose radiation therapy is more effective than standard-dose radiation therapy when given together with combination chemotherapy with or without cetuximab in treating patients with non-small cell lung cancer. PURPOSE: This randomized phase III trial is studying high-dose or standard-dose radiation therapy given together with chemotherapy with or without cetuximab to see how well they work in treating patients with newly diagnosed stage III non-small cell lung cancer that cannot be removed by surgery.

Detailed Description

OBJECTIVES: Primary To compare the overall survival of patients with newly diagnosed, unresectable stage IIIA or IIIB non-small cell lung cancer treated with high- versus standard-dose conformal radiotherapy with concurrent and consolidation chemotherapy comprising carboplatin and paclitaxel. To compare the overall survival of patients treated with versus without cetuximab in the setting of concurrent chemotherapy Secondary To compare progression-free survival and local-regional tumor control in patients treated with these regimens. To compare the toxicity of high- versus standard-dose conformal radiotherapy and concurrent chemotherapy with versus without cetuximab in these patients. To investigate the prognostic and predictive effects of gross tumor volume on overall survival of patients treated with these regimens. To compare the quality of life of patients treated with these regimens. To correlate outcomes (i.e., survival, toxicity, or QOL) in these patients with biological parameters. To analyze the predictive value of pre-treatment standardized uptake value (SUV) of positron emission tomography (PET) scan in predicting survival, distant metastasis, and local-regional control in patients treated with these regimens. To explore biological markers to predict clinical outcome including survival, distant metastasis, local-regional control, and QOL (including toxicity) in patients treated with these regimens. To prospectively collect and bank tissue, blood, and urine specimens for future biomarker analyses in predicting clinical outcome in patients treated with these regimens. To investigate associations between epidermal growth factor receptor (EGFR) expression and toxicity, response, overall survival, and progression-free survival. OUTLINE: This is a multicenter study. Patients are stratified according to PET staging (yes vs no), radiotherapy technique (3-dimensional conformal radiotherapy vs intensity-modulated radiotherapy), Zubrod performance status (0 vs 1), and histology (squamous vs non-squamous). Patients are randomized to 1 of 4 treatment arms. (Arms II and IV closed to accrual effective 6/17/11) Patients may undergo tumor tissue, blood, and urine collection periodically during study for tissue banking or biomarker correlative studies. Patients may undergo quality-of-life assessment at baseline and periodically during study. After completion of study therapy, patients are followed periodically for 5 years and then annually thereafter.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Lung Cancer, Radiation Toxicity

Keywords

radiation toxicity, stage IIIA non-small cell lung cancer, stage IIIB non-small cell lung cancer

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Crossover Assignment

Model Description

This study was revised 06/18/08 to a 2x2 factorial design to evaluate the addition of cetuximab to the radiation therapy regimens.

Masking

None (Open Label)

Allocation

Randomized

Enrollment

544 (Actual)

8. Arms, Groups, and Interventions

Arm Title

60 Gy RT

Arm Type

Active Comparator

Arm Description

60 Gy Radiation therapy with concurrent paclitaxel and carboplatin followed by consolidation paclitaxel and carboplatin

Arm Title

74 Gy RT

Arm Type

Experimental

Arm Description

74 Gy Radiation therapy with concurrent paclitaxel and carboplatin followed by consolidation paclitaxel and carboplatin

Arm Title

60 Gy RT + Cetuximab

Arm Type

Experimental

Arm Description

60 Gy Radiation therapy with concurrent cetuximab, paclitaxel, and carboplatin followed by consolidation cetuximab, paclitaxel, and carboplatin

Arm Title

74 Gy RT + Cetuximab

Arm Type

Experimental

Arm Description

74 Gy Radiation therapy with concurrent cetuximab, paclitaxel, and carboplatin followed by consolidation cetuximab, paclitaxel, and carboplatin

Intervention Type

Biological

Intervention Name(s)

Cetuximab

Other Intervention Name(s)

Erbitux

Intervention Description

Loading dose: 400 mg/m2, IV, one week prior to start of radiation therapy (RT). Then, beginning day 1 of RT, 250 mg/m2, IV, weekly; for 60 Gy arm for 15 weeks, for 74 Gy arm for 16 weeks.

Intervention Type

Drug

Intervention Name(s)

Carboplatin

Other Intervention Name(s)

Paraplatin

Intervention Description

Concurrent: AUC=2, IV, days 1, 8, 14, 22, 29, and 36 of radiation therapy; for 74 Gy arms, on day 43 as well. Consolidation, 3 weeks after completion of RT, AUC=6, IV, days 1 and 22.

Intervention Type

Drug

Intervention Name(s)

Paclitaxel

Other Intervention Name(s)

Taxol, Abraxane

Intervention Description

Concurrent: 45 mg/m2, IV, days 1, 8, 14, 22, 29, and 36 of radiation therapy (RT); for 74 Gy arms, on day 43 as well. Consolidation, 3 weeks after completion of RT, 200 mg/m2, IV, days 1 and 22.

Intervention Type

Radiation

Intervention Name(s)

60 Gy RT

Other Intervention Name(s)

Intervention Description

Radiation therapy (RT) in once-daily, 2 Gy fractions, given in 30 fractions over the course of 6 weeks.

Intervention Type

Radiation

Intervention Name(s)

74 Gy RT

Intervention Description

Radiation therapy (RT) in once-daily, 2 Gy fractions, given in 37 fractions over the course of 7.5 weeks.

Primary Outcome Measure Information:

Title

Overall Survival

Description

Time Frame

From randomization to last follow-up. Analysis occured after all patients were on study for 18 months. Maximum follow-up at time of analysis was 61.5 months.

Secondary Outcome Measure Information:

Title

Progression-free Survival

Description

Time Frame

From randomization to last follow-up. Analysis occured after all patients were on study for 18 months. Maximum follow-up at time of analysis was 61.5 months.

Title

Local-regional Failure (Reported as Two-year Estimates)

Description

Time Frame

From randomization to last follow-up. Analysis occured after all patients were on study for 18 months. Maximum follow-up at time of analysis was 61.5 months.

Title

Percentage of Participants With Grade 3-5 Esophagitis and Pneumonitis Adverse Events as Assessed by NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v3.0

Description

Time Frame

From randomization to last follow-up. Analysis occured after all patients were on study for 18 months. Maximum follow-up at time of analysis was 61.5 months.

Title

Percentage of Participants With Other Grade 3-5 Adverse Events as Assessed by NCI CTCAE v3.0

Description

Time Frame

From randomization to last follow-up. Analysis occured after all patients were on study for 18 months. Maximum follow-up at time of analysis was 61.5 months.

Title

Death During or Within 30 Days of Discontinuation of Protocol Treatment

Description

Deaths regardless of cause and occuring during or within 30 days of discontinuation of protocol treatment were evaluated.

Time Frame

From start of protocol treatment to 24 months.

Title

Percentage of Patients With Decline From Baseline to 3 Months in the Lung Cancer Subscale (LCS) of the Functional Assessment of the Cancer Therapy Trial Outcome Index (FACT-TOI).

Description

Time Frame

At baseline and 3 months.

Title

Patient-reported Swallowing Score (Area Under the Curve)

Description

Time Frame

From randomization to 6 weeks after start of radiation therapy (6-10 weeks from randomization)

Title

EuroQoL (EQ5D) Visual Analog Scale (VAS) Through One Year (Area Under the Curve)

Description

Time Frame

From randomization to one year

Title

Overall Survival and Local-regional Failure by Epithelial Growth Factor Receptor (EGFR) Group

Description

Time Frame

From randomization to last follow-up. Analysis occured after all patients were on study for 18 months. Maximum follow-up at time of analysis was 61.5 months.

Title

Percentage of Patients With Grade 3+ Adverse Events by Epithelial Growth Factor Receptor (EGFR) Group

Description

EGFR is a protein that is present on the surface of both normal cells and cancer cancer cells. EGFR H-Score is a measure of staining intensity ranging from 0 to 300 where a higher value indicates greater intensity of EGFR. Available tumor samples were evaluated for EGFR and given an H-Score. Patients were divided into two groups based on H-Score values dichotomized at 200. Worst toxicity as determined by adverse events was used as a measure of a patient's quality of life (QOL). Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE 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 AE. Highest grade (worst) adverse event (AE) per subject was counted.

Time Frame

From randomization to last follow-up. Analysis occured after all patients were on study for 18 months. Maximum follow-up at time of analysis was 61.5 months.

Title

Prognostic and Predictive Effects of Gross Tumor Volume (GTV) on Overall Survival

Description

Time Frame

From randomization to last follow-up. Analysis occured after all patients were on study for 18 months. Maximum follow-up at time of analysis was 61.5 months.

Title

Prognostic Value of Pre-treatment Standardized Uptake Value (SUV) of Positron Emission Tomography (PET) Scan in Predicting Survival, Distant Metastasis, and Local-regional Failure

Description

Time Frame

From randomization to last follow-up. Analysis occured after all patients were on study for 18 months. Maximum follow-up at time of analysis was 61.5 months.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion criteria: Pathologically proven (either histologic or cytologic) diagnosis of Stage IIIA or IIIB non-small cell lung cancer (NSCLC); excluding patients with N3 disease based on supraclavicular or contralateral hilar adenopathy, [according to American Joint Committee on Cancer (AJCC) Staging, 6th edition; see appendix III] within 12 weeks of registration; patients who present with N2 or N3 disease and an undetectable NSCLC primary tumor also are eligible. Patients must be considered unresectable or inoperable; Note: Patients who have had a nodal recurrence after surgery for an early-stage NSCLC are eligible if the following criteria are met: Nodal recurrence must be N1 or N2; N3 is not eligible. The initial primary must have been staged as T1-2, N0, M0. The node must be biopsied within 12 weeks of registration. The node must be measurable. The patient must not have received prior chemotherapy or radiation for this lung cancer. Prior curative surgery must have been at least 6 months prior to the nodal recurrence. The exception to a prior invasive malignancy does not apply to the initial lung primary. Stage III A or B disease, including no distant metastases, based upon the following minimum diagnostic workup are acceptable: History/physical examination, including documentation of height, weight, body surface area (BSA), and vital signs within 8 weeks prior to registration; Computed tomographic (CT)/Magnetic Resonance Imaging (MRI) imaging of the lung and upper abdomen through the adrenal glands within 6 weeks prior to registration; An MRI of the brain with contrast (or CT with contrast if MRI is medically contraindicated) within 6 weeks prior to registration; Note: The use of intravenous contrast is required for the MRI or CT. An MRI without contrast is only permitted if the patient has a contrast allergy. Whole-body fluorodeoxyglucose (FDG) - Positron Emission Tomography(PET) or PET/CT or if no PET is available, a bone scan is required within 6 weeks prior to registration; Note: If a PET is done that shows clear adrenals and lungs, then a CT scan of chest only is permitted. If a pleural effusion is present, the following criteria must be met to exclude malignant involvement (incurable T4 disease): When pleural fluid is visible on both the CT scan and on a chest x-ray, a pleuracentesis is required to confirm that the pleural fluid is cytologically negative. Exudative pleural effusions are excluded, regardless of cytology; Effusions that are minimal (i.e. not visible on chest x-ray) that are too small to safely tap are eligible. Patients must have measurable or evaluable disease. Patients with post-obstructive pneumonia are eligible. Patients must be at least 3 weeks from prior thoracotomy (if performed). Zubrod Performance Status 0-1; Age ≥ 18; Pulmonary function tests (PFTs) including forced expiratory volume in one second (FEV1) within 12 weeks prior to registration; for FEV1, the best value obtained pre- or post bronchodilator must be ≥ 1.2 liters/second or ≥ 50% predicted. Complete blood count (CBC)/differential obtained within 2 weeks prior to registration on study, with adequate bone marrow function defined as follows: Absolute neutrophil count (ANC) ≥ 1,800 cells/mm3; Platelets ≥ 100,000 cells/mm3; Hemoglobin ≥ 10.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 10.0 g/dl is acceptable.) Serum creatinine within normal institutional limits or creatinine clearance ≥60 ml/min; Bilirubin must be within or below normal institutional limits; Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) < 2.5 x the institutional upper limit of normal (IULN); Patient must sign study specific informed consent prior to study entry. Exclusion Criteria: N3 supraclavicular disease; Greater than minimal, exudative, or cytologically positive pleural effusions; Involved contralateral hilar nodes (i.e. greater than 1.5 cm on short axis or positive on PET scan); ≥ 10% weight loss within the past month; Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years; non-invasive conditions such as carcinoma in situ of the breast, oral cavity, or cervix are all permissible. Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable. Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields; Prior therapy that specifically and directly targets the epidermal growth factor receptor (EGFR) pathway; Prior severe infusion reaction to a monoclonal antibody; Severe, active co-morbidity, defined as follows: Significant history of uncontrolled cardiac disease; i.e., uncontrolled hypertension, unstable angina, myocardial infarction within the last 6 months, uncontrolled congestive heart failure, and cardiomyopathy with decreased ejection fraction. Transmural myocardial infarction within the last 6 months; Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration; Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before registration; Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive. Protocol-specific requirements may also exclude immuno-compromised patients. Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic. Any history of allergic reaction to paclitaxel or other taxanes, or to carboplatin; Uncontrolled neuropathy grade 2 or greater regardless of cause.

Overall Study Officials: