Positron Emission Tomography and Computed Tomography in Guiding Radiation Therapy for Stage III Non-small Cell Lung Cancer

Randomized Phase II Trial of Individualized Adaptive Radiotherapy Using During-Treatment FDG-PET/CT and Modern Technology in Locally Advanced Non-Small Cell Lung Cancer (NSCLC)

This randomized phase II trial studies how well positron emission tomography (PET)/computed tomography (CT)-guided radiation therapy works compared to standard radiation therapy in treating patients with stage III non-small cell lung cancer. Radiation therapy uses high-energy x-rays to kill tumor cells. Using imaging procedures, such as PET and CT scans, to guide the radiation therapy, may help doctors deliver higher doses directly to the tumor and cause less damage to healthy tissue.

Study Overview

• Status: Completed
• Conditions: Stage IIIA Lung Non-Small Cell Cancer AJCC v7; Stage IIIB Lung Non-Small Cell Cancer AJCC v7; Stage III Lung Non-Small Cell Cancer AJCC v7
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Carboplatin; Drug: Paclitaxel; Procedure: Computed Tomography; Procedure: Positron Emission Tomography; Drug: Fludeoxyglucose F-18; Radiation: External Beam Radiation Therapy; Drug: 18F-Fluoromisonidazole; Procedure: Computed Tomography; Procedure: Positron Emission Tomography; Radiation: Image-Guided Adaptive Radiation Therapy

Detailed Description

PRIMARY OBJECTIVES:

I. To determine whether tumor dose can be escalated to improve the freedom from local-regional progression-free (LRPF) rate at 2 years when an individualized adaptive radiation treatment (RT) plan is applied by the use of a fludeoxyglucose F 18 (FDG)-positron emission tomography (PET)/computed tomography (CT) scan acquired during the course of fractionated RT in patients with inoperable stage III non-small cell lung cancer (NSCLC). (National Surgical Adjuvant Breast and Bowel Project [NSABP], Radiation Therapy Oncology Group [RTOG], Gynecologic Oncology Group [GOG] [NRG] Oncology) II. To determine whether the relative change in standard uptake value (SUV) peak from the baseline to the during-treatment FDG-PET/CT, defined as (during-treatment SUVpeak - baseline SUVpeak)/baseline SUV peak x 100%, can predict the LRPF rate with a 2-year follow up. (Eastern Cooperative Oncology Group [ECOG]-American College of Radiology Imaging Network [ACRIN])

SECONDARY OBJECTIVES:

I. To determine whether an individualized dose escalation improves overall survival (OS), progression-free survival (PFS), lung cancer cause-specific survival, and delays time to local-regional progression compared to a conventional RT plan. (NRG Oncology) II. To compare the rate of severe (grade 3+ Common Terminology Criteria for Adverse Events [CTCAE], v. 4) radiation-induced lung toxicity (RILT) defined as severe RILT pneumonitis or clinical fibrosis. (NRG Oncology) III. To compare other severe adverse events, including grade 3+ (CTCAE, v. 4) esophagitis or grade 2 pericardial effusions, or any grade cardiac adverse events related to chemoradiation between a PET/CT-guided adaptive approach and a conventional RT plan. (NRG Oncology) IV. To evaluate the association of baseline 18F-fluoromisonidazole (FMISO), a PET/CT imaging agent, uptake (tumor-to-blood pool ratio) with LRPF (i.e., the assessment of using baseline FMISO-PET uptake as a prognostic marker). (ECOG-ACRIN) V. To determine if the relative change in SUVpeak from baseline to during-treatment FDG-PET/CT and/or baseline FMISO uptake (tumor-to-blood pool ratio) predicts the differential benefit of the adaptive therapy, i.e., the association of uptake parameters with LRPF rate depending on the assigned treatment thus, assessing if these uptake parameters can be useful in guiding therapies, i.e., predictive markers. (ECOG-ACRIN) VI. To determine if other PET-imaging uptake parameters (SUV peak during-treatment for FDG-PET, maximum SUV, or relative change of maximum SUVs from pre- to during-treatment FDG-PET/CT, change in metabolic tumor volume, FMISO total hypoxic volume, FMISO tumor to mediastinum ratio, EORTC or University of Michigan/Kong's response criteria) will predict OS, LRPF rate, and lung cancer cause-specific (LCS) survival as well as to explore the optimal threshold for differentiating responders from non-responders. (ECOG-ACRIN)

CORRELATIVE SCIENCE OBJECTIVES:

I. To study whether a model of combining current clinical and/or imaging factors with blood markers, including osteopontin (OPN) [for hypoxia marker], carcinoembryonic antigen (CEA) and cytokeratin fragment (CYFRA) 21-1 (for tumor burden), and interleukin (IL)-6 (inflammation) will predict the 2-year LRPF rate and survival better than a current model using clinical factors and radiation dose as well as imaging factors.

II. To determine/validate whether a model of combining mean lung dose (MLD), transforming growth factor beta1 (TGF beta1) and IL-8 will improve the predictive accuracy for clinical significant RILT better comparing to the current model of using MLD alone.

III. To explore, in a preliminary manner, whether proteomic and genomic markers in the blood prior to and during the early course of treatment are associated with tumor response after completion of treatment, LRPF rate, PFS, OS, and pattern of failure and treatment-related adverse events, such as radiation pneumonitis, esophagitis, and pericardial effusion. (exploratory)

OUTLINE:

Prior to treatment, patients undergo fludeoxyglucose F 18 (FDG) positron emission tomography (PET) and computed tomography (CT) scans at baseline and periodically during study. A subset of patients also undergo 18F-fluoromisonidazole PET/CT scan at baseline. Patients are randomized to 1 of 2 treatment arms:

ARM I (standard chemoradiotherapy): Patients undergo radiotherapy once daily (QD) 5 days a week for 30 fractions. Patients also receive paclitaxel intravenously (IV) over 1 hour and carboplatin IV over 30 minutes once weekly for 6 weeks. Patients undergo FDG-PET/CT imaging between fractions 18 and 19.

ARM II (experimental chemoradiotherapy): Patients undergo an individualized dose of image-guided radiotherapy QD 5 days a week for 30 fractions and undergo 18 F FDG-PET/CT between fractions 18 and 19. Based on the scan results, patients undergo individualized adaptive radiotherapy for the final 9 fractions. Patients also receive paclitaxel and carboplatin as in Arm I.

CONSOLIDATION CHEMOTHERAPY: Beginning 4-6 weeks after chemoradiotherapy, patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 1 month, every 3 months for 1 year, every 6 months for 2 years, and then annually for 2 years.

• Study Type: Interventional
• Enrollment (Actual): 138
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H2W 1S6
      • McGill University Department of Oncology
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7N 4H4
      • Saskatoon Cancer Centre
• United States
  • California
    • Palo Alto, California, United States, 94304
      • Stanford Cancer Institute Palo Alto
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Augusta University Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University/Melvin and Bren Simon Cancer Center
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • The James Graham Brown Cancer Center at University of Louisville
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Comprehensive Cancer Center
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Saint Luke's Hospital of Kansas City
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New Jersey
    • Basking Ridge, New Jersey, United States, 07920
      • Memorial Sloan Kettering Basking Ridge
  • New York
    • Commack, New York, United States, 11725
      • Memorial Sloan Kettering Commack
    • Harrison, New York, United States, 10604
      • Memorial Sloan Kettering Westchester
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • Sleepy Hollow, New York, United States, 10591
      • Memorial Sloan Kettering Sleepy Hollow
    • Uniondale, New York, United States, 11553
      • Memorial Sloan Kettering Nassau
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve University
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Cleveland, Ohio, United States, 44111
      • Cleveland Clinic Cancer Center/Fairview Hospital
    • Independence, Ohio, United States, 44131
      • Cleveland Clinic Cancer Center Independence
    • Mayfield Heights, Ohio, United States, 44124
      • Hillcrest Hospital Cancer Center
    • Strongsville, Ohio, United States, 44136
      • Cleveland Clinic Cancer Center Strongsville
    • Wooster, Ohio, United States, 44691
      • Cleveland Clinic Wooster Family Health and Surgery Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital
    • West Reading, Pennsylvania, United States, 19611
      • Reading Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Carbone Cancer Center
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients must have FDG-avid (maximum SUV >= 4.0) (from PET scan of any date, any scanner) and histologically or cytologically proven non-small cell lung cancer
• Patients must be clinical American Joint Committee on Cancer (AJCC) stage IIIA or IIIB (AJCC, 7th ed.) with non-operable disease; non-operable disease will be determined by a multi-disciplinary treatment team, involving evaluation by at least 1 thoracic surgeon within 8 weeks prior to registration; Note: For patients who are clearly nonresectable, the case can be determined by the treating radiation oncologist and a medical oncologist, or pulmonologist
• Patients with multiple, ipsilateral pulmonary nodules (T3 or T4) are eligible if a definitive course of daily fractionated radiation therapy (RT) is planned
• History/physical examination, including documentation of weight, within 2 weeks prior to registration
• FDG-PET/CT scan for staging and RT plan within 4 weeks prior to registration
• CT scan or sim CT of chest and upper abdomen (IV contrast is recommended unless medically contraindicated) within 6 weeks prior to registration
• CT scan of the brain (contrast is recommended unless medically contraindicated) or MRI of the brain within 6 weeks prior to registration
• Pulmonary function tests, including diffusion capacity of carbon monoxide (DLCO), within 6 weeks prior to registration; patients must have forced expiratory volume in 1 second (FEV1) >= 1.2 Liter or >= 50% predicted without bronchodilator
• Zubrod performance status 0-1
• Able to tolerate PET/CT imaging required to be performed at an American College of Radiology (ACR) Imaging Core Laboratory (Lab) qualified facility
• Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 (within 2 weeks prior to registration on study)
• Platelets >= 100,000 cells/mm^3 (within 2 weeks prior to registration on study)
• Hemoglobin (Hgb) >= 10.0 g/dL (note: the use of transfusion or other intervention to achieve Hgb >= 10.0 g/dL is acceptable) (within 2 weeks prior to registration on study)
• Serum creatinine within normal institutional limits or a creatinine clearance >= 60 ml/min within 2 weeks prior to registration
• Negative serum or urine pregnancy test within 3 days prior to registration for women of childbearing potential
• Women of childbearing potential and male participants must agree to use a medically effective means of birth control throughout their participation in the treatment phase of the study
• The patient must provide study-specific informed consent prior to study entry

Exclusion Criteria:

• Patients with any component of small cell lung carcinoma are excluded
• Patients with evidence of a malignant pleural or pericardial effusion are excluded
• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years (for example, 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

• Severe, active co-morbidity, defined as follows:

  • Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
  • 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 at the time of registration
  • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol
  • Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol
• Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception
• Poorly controlled diabetes (defined as fasting glucose level > 200 mg/dL) despite attempts to improve glucose control by fasting duration and adjustment of medications; patients with diabetes will preferably be scheduled in the morning and instructions for fasting and use of medications will be provided in consultation with the patients' primary physicians
• Patients with T4 disease with radiographic evidence of massive invasion of a large pulmonary artery and tumor causing significant narrowing and destruction of that artery are excluded

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm I (standard chemoradiotherapy); Patients undergo radiotherapy QD 5 days a week for 30 fractions. Patients also receive paclitaxel IV over 1 hour and carboplatin IV over 30 minutes once weekly for 6 weeks. Patients undergo FDG-PET/CT imaging between fractions 18 and 19.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Carboplatin; Given IV; Other Names: Blastocarb; Carboplat; Carboplatin Hexal; Carboplatino; Carboplatinum; Carbosin; Carbosol; Carbotec; CBDCA; Displata; Ercar; JM-8; Nealorin; Novoplatinum; Paraplatin; Paraplatin AQ; Paraplatine; Platinwas; Ribocarbo; Drug: Paclitaxel; Given IV; Other Names: Taxol; Anzatax; Asotax; Bristaxol; Praxel; Taxol Konzentrat; Procedure: Computed Tomography; Undergo FDG PET/CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Procedure: Positron Emission Tomography; Undergo FDG PET/CT; Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; proton magnetic resonance spectroscopic imaging; Drug: Fludeoxyglucose F-18; Undergo FDG PET/CT; Other Names: 18FDG; FDG; fludeoxyglucose F 18; Fludeoxyglucose (18F); Fludeoxyglucose F18; Fluorine-18 2-Fluoro-2-deoxy-D-Glucose; Fluorodeoxyglucose F18; Radiation: External Beam Radiation Therapy; Undergo radiotherapy; Other Names: EBRT; Definitive Radiation Therapy; External Beam Radiation; External Beam Radiotherapy; External Beam RT; external radiation; External Radiation Therapy; external-beam radiation; Radiation, External Beam; Teleradiotherapy; Teletherapy; Teletherapy Radiation; Drug: 18F-Fluoromisonidazole; Undergo FMISO PET/CT (Correlative studies); Other Names: FMISO; 18F-MISO; 18F-Misonidazole; FLUOROMISONIDAZOLE F-18; Procedure: Computed Tomography; Undergo FMISO PET/CT (Correlative studies); Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Procedure: Positron Emission Tomography; Undergo FMISO PET/CT (Correlative studies); Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; proton magnetic resonance spectroscopic imaging
Experimental: Arm II (experimental chemoradiotherapy); Patients undergo an individualized dose of image-guided radiotherapy QD 5 days a week for 30 fractions and undergo 18 F FDG-PET/CT between fractions 18 and 19. Based on the scan results, patients undergo individualized adaptive radiotherapy for the final 9 fractions. Patients also receive paclitaxel and carboplatin as in Arm I.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Carboplatin; Given IV; Other Names: Blastocarb; Carboplat; Carboplatin Hexal; Carboplatino; Carboplatinum; Carbosin; Carbosol; Carbotec; CBDCA; Displata; Ercar; JM-8; Nealorin; Novoplatinum; Paraplatin; Paraplatin AQ; Paraplatine; Platinwas; Ribocarbo; Drug: Paclitaxel; Given IV; Other Names: Taxol; Anzatax; Asotax; Bristaxol; Praxel; Taxol Konzentrat; Procedure: Computed Tomography; Undergo FDG PET/CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Procedure: Positron Emission Tomography; Undergo FDG PET/CT; Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; proton magnetic resonance spectroscopic imaging; Drug: Fludeoxyglucose F-18; Undergo FDG PET/CT; Other Names: 18FDG; FDG; fludeoxyglucose F 18; Fludeoxyglucose (18F); Fludeoxyglucose F18; Fluorine-18 2-Fluoro-2-deoxy-D-Glucose; Fluorodeoxyglucose F18; Drug: 18F-Fluoromisonidazole; Undergo FMISO PET/CT (Correlative studies); Other Names: FMISO; 18F-MISO; 18F-Misonidazole; FLUOROMISONIDAZOLE F-18; Procedure: Computed Tomography; Undergo FMISO PET/CT (Correlative studies); Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Procedure: Positron Emission Tomography; Undergo FMISO PET/CT (Correlative studies); Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; proton magnetic resonance spectroscopic imaging; Radiation: Image-Guided Adaptive Radiation Therapy; Undergo individualized adaptive radiotherapy; Other Names: IGART

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Alive Without Local-regional Progression [Local-regional Progression-free (LRPF) Survival] at Two Years (NRG)	LRPF survival is defined as survival without local-regional progression (LRP) as determined by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria with integration of 8F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT), and reviewed centrally based on submitted CT scans. LRP is defined as any of the following: ≥ 20% increase in any of the target lesions (primary and nodal disease),; ≥ 20% increase in the peak SUV of target lesions,; appearance of one or more new lesions within previously irradiated regions. LRPF-free survival time is defined as time from registration to the date of first local-regional progression, distant recurrence (censored), death without documented LRP (censored), or death. LRPF survival rates are estimated using the Kaplan-Meier method.	Randomization to 2 years
Relative Change in SUVpeak From the Baseline to the During-treatment Fludeoxyglucose F 18 (FDG)-Positron Emission Tomography (PET)/Computed Tomography (CT) to LRPF With a 2-year Follow up. (ECOG-ACRIN)	To determine whether the relative change in SUVpeak (from the baseline to the during-treatment FDG-PET/CT) can predict the LRPF with a 2-year follow up. Relative ΔSUVpeak = (Mid-treatment SUVpeak - baseline SUVpeak)/baseline SUVpeak x 100 LRPF was determined from Randomization up to 2 years	Baseline to during-treatment (approximately between fractions 18-19) Randomization to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Local-regional Progression (NRG)	Local-regional progression (LRP) is determined by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria with integration of 8F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT), and reviewed centrally based on submitted CT scans. LRP is defined as any of the following: ≥ 20% increase in any of the target lesions (primary and nodal disease),; ≥ 20% increase in the peak SUV of target lesions,; appearance of one or more new lesions within previously irradiated regions. LRP time is defined as time from randomization to the date of first LRP, distant metastasis without LRP (competing risk), death without LRP (competing risk), or last known follow-up (censored). LRP rates are estimated using the cumulative incidence method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Two-year rates are provided.	From randomization to last follow-up: weekly during treatment, then 1, 3, 6, 9, 12, 18, 24, 30, 36, 48, and 60 months after end of protocol treatment, then annually. Maximum follow-up at time of reporting was 7.3 years. Two-year rates reported here.
Percentage of Participants Alive (Overall Survival) (NRG)	Overall survival time is defined as time from randomization to the date of death from any cause or last known follow-up (censored). Survival rates are estimated using the Kaplan-Meier method. The protocol specifies that the distributions of survival times be compared between the arms, which is reported in the statistical analysis results. Two-year rates are provided.	From randomization to last follow-up: weekly during treatment, then 1, 3, 6, 9, 12, 18, 24, 30, 36, 48, and 60 months after end of protocol treatment, then annually. Maximum follow-up at time of reporting was 7.3 years. Two-year rates reported here.
Percentage of Participants Alive Without Progression (Progression-free Survival) (NRG)	Progression is defined as the first of the following: local, regional, distant progression, or death due to any cause. Progression-free survival time is defined as time from randomization to the date of first progression, death, or last known follow-up (censored). Progression-free survival rates are estimated using the Kaplan-Meier method. Two-year estimates are provided.	From randomization to last follow-up: weekly during treatment, then 1, 3, 6, 9, 12, 18, 24, 30, 36, 48, and 60 months after end of protocol treatment, then annually. Maximum follow-up at time of reporting was 7.3 years. Two-year rates reported here.
Percentage of Participants With Death Due to Lung Cancer (NRG)	A lung cancer death is defined as cause of death designated as lung cancer or death with any evidence of disease progression at any site without a direct evidence of other cause of death. Time to lung cancer death is defined as time from randomization to the date of lung cancer death, last known follow-up (censored), or death without lung cancer (competing risk). Lung cancer death rates are estimated using the cumulative incidence method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Two-year rates are provided.	From randomization to last follow-up: weekly during treatment, then 1, 3, 6, 9, 12, 18, 24, 30, 36, 48, and 60 months after end of protocol treatment, then annually. Maximum follow-up at time of reporting was 7.3 years. Two-year rates reported here.
Percentage of Participants With Grade 3+ Radiation-induced Lung Toxicity [RILT] at Any Time (NRG)	RILT is defined as clinical radiation pneumonitis and clinical fibrosis. Grading is defined in the protocol as follows (grade 3 and higher): Clinical pneumonitis:Grade 3: Severe cough, unresponsive to narcotic antitussive agent and /or dyspnea at rest, with radiographic evidence of acute pneumonitis, and requiring oxygen (intermittent or continuous) for treatment;Grade 4: Radiation pneumonitis causes respiratory insufficiency, requiring assisted ventilation;Grade 5: Radiation pneumonitis directly contributes to the cause of the death;; Clinical fibrosis:Grade 3: Radiographic evidence of radiation fibrosis causing dyspnea at rest, interfering with activities of daily living, and home oxygen indicated;Grade 4: Radiation fibrosis causes respiratory insufficiency, requiring assisted ventilation;Grade 5: Radiation fibrosis directly contributes to the cause of the death.	From randomization to last follow-up: weekly during treatment, then 1, 3, 6, 9, 12, 18, 24, 30, 36, 48, and 60 months after end of protocol treatment, then annually. Maximum follow-up at time of reporting was 7.3 years.
Percentage of Participants With Grade 3+ Esophagitis, Pericardial Effusion, and Any Cardiac Adverse Events at Any Time (NRG)	Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity from 1=mild to 5=death. Summary data is provided in this outcome measure; See Adverse Events Module for specific adverse event data.	From randomization to last follow-up: weekly during treatment, then 1, 3, 6, 9, 12, 18, 24, 30, 36, 48, and 60 months after end of protocol treatment, then annually. Maximum follow-up at time of reporting was 7.3 years.
Baseline 18F-fluoromisonidazole (FMISO) Uptake (Tumor-to-blood Pool Ratio) Measures Association With LRPF 2-years Post Registration (ECOG-ACRIN)	Baseline PET-MISO measures are normalized to blood uptake (ie., tumor-to-blood pool ratio) : Tumor SUV Mean, Tumor SUV Max, Tumor SUV Peak Association with LRPF 2-years post registration (That is, evaluate baseline FMISO-PET uptake as a prognostic marker of LRPF)	Baseline and 2-years after randomization
Baseline 18F-fluoromisonidazole (FMISO) Tumor Hypoxic Volume Association With LRPF 2-years Post Registration (ECOG-ACRIN)	Tumor Hypoxic Volume (PET-MISO measure) is defined as the number of pixels in the gross tumor volume with a tumor-to-blood pool ratio of > 1.2, Association With LRPF 2-years Post Registration	Baseline and 2-years after randomization
Relative Change in SUV Peak From the Baseline to the During-treatment FDG PET/CT Prediction of the Differential Benefit of the Adaptive Therapy (ECOG-ACRIN)	Relative change in SUVpeak defined as ΔSUVpeak = (during-treatment SUVpeak - baseline SUVpeak)/baseline SUVpeak x 100%), Outcomes evaluated at 5 years. Overall Survival (OS): True if Alive 5 years from registration Progression Free Survival (PFS): True if Alive and no Progression 5 years from registration Lung Cancer Cause-specific Survival (LCCS): True if Alive and no Lung Cancer 5 years from registration	Baseline to up to 5 years after randomization
SUVmax at Baseline Prediction of OS and Optimal Threshold (ECOG-ACRIN)	FDG SUVmax as measured at baseline PET imaging will be assessed in its ability to predict Overall Survival (OS) at year 5.	Baseline to up to 5 years
FDG ΔSUVmax, From Baseline to the During-treatment FDG PET/CT, to Predict OS and Optimal Threshold (ECOG-ACRIN)	FDG ΔSUVmax as measured at baseline PET imaging will be assessed in its ability to predict Overall Survival (OS) at year 5. Relative change in FDG SUVmax defined as ΔSUVmax = (during-treatment SUVmax - baseline SUVmax )/baseline SUVmax x 100%), Outcomes evaluated at 5 years. Overall Survival (OS): True if Alive 5 years from registration.	Baseline to up to 5 years
ΔSUVpeak Prediction of Overall Survival, Progression Free Survival, and Lung Cancer Cause-specific Survival (ECOG-ACRIN)	ΔSUVpeak will be measured as 100* (SUVpeak Mid-treatment - SUVpeak baseline)/(SUVpeak baseline) All survival measures will be measured in days from registration up to 5 years.	Up to 5 years
FDG ΔSUVpeak From Baseline to the During-treatment FDG PET/CT, to Predict Overall Survival and Optimal Threshold (ECOG-ACRIN)	FDG ΔSUVpeak, as measured from Baseline to the During-treatment FDG PET/CT, will be assessed in its ability to predict Overall Survival (OS) and an Optimal Threshold (OT) for differentiating responders from non-responders will be identified ΔSUVpeak defined as ((during-treatment measure - baseline measure)/baseline measure) x 100%) OS defined as Alive 5 years post registration (Responders) OT defined as the ΔSUVpeak value corresponding to the maximum Youden index	Baseline to up to 5 years
FDG ΔMTV From Baseline to the During-treatment FDG PET/CT, to Predict Overall Survival and Optimal Threshold (ECOG-ACRIN)	FDG ΔMTV, as measured from Baseline to the During-treatment FDG PET/CT, will be assessed in its ability to predict Overall Survival (OS) and an Optimal Threshold (OT) for differentiating responders from non-responders will be identified FDG ΔMTV defined as ((during-treatment measure - baseline measure)/baseline measure) x 100%) OS defined as Alive 5 years post registration (Responders) OT defined as the ΔMTV value corresponding to the maximum Youden index	Baseline to up to 5 years
FMISO Hypoxic Tumor Volume (HV) @Baseline, to Predict Overall Survival and Optimal Threshold (ECOG-ACRIN)	FMISO Hypoxic tumor volume @baseline, will be assessed in its ability to predict Overall Survival (OS) and an Optimal Threshold (OT) for differentiating responders from non-responders will be identified HV defined as the number of pixels in the gross tumor volume with a tumor-to-blood pool ratio of > 1.2 in cc OS defined as Alive 5 years post registration (Responders) OT defined as the HV value corresponding to the maximum Youden index	Baseline to up to 5 years
FDG SUVmax @ Baseline FDG PET/CT, to Predict Lung Cancer Cause-specific Survival and Optimal Threshold (ECOG-ACRIN)	SUVmax, as measured at Baseline, will be assessed in its ability to predict Lung Cancer Cause-specific Survival (LCCS) and an Optimal Threshold (OT) for differentiating responders from non-responders will be identified LCCS defined as NO Lung Cancer Cause-specific disease 5 years post registration (Responders) OT defined as the SUVmax value corresponding to the maximum Youden index	Baseline to up to 5 years
FDG ΔSUVmax From Baseline to the During-treatment FDG PET/CT, to Predict Lung Cancer Cause-specific Survival and Optimal Threshold (ECOG-ACRIN)	FDG ΔSUVmax, as measured from Baseline to the During-treatment FDG PET/CT, will be assessed in its ability to predict Lung Cancer Cause-specific Survival (LCCS) and an Optimal Threshold (OT) for differentiating responders from non-responders will be identified ΔSUVmax defined as ((during-treatment measure - baseline measure)/baseline measure) x 100%) LCCS defined as NO Lung Cancer Cause-specific disease 5 years post registration (Responders) OT defined as the ΔSUVmax value corresponding to the maximum Youden index	Baseline to up to 5 years
FDG ΔSUVpeak From Baseline to the During-treatment FDG PET/CT, to Predict Lung Cancer Cause-specific Survival and Optimal Threshold (ECOG-ACRIN)	FDG ΔSUVpeak, as measured from Baseline to the During-treatment FDG PET/CT, will be assessed in its ability to predict Lung Cancer Cause-specific Survival (LCCS) and an Optimal Threshold (OT) for differentiating responders from non-responders will be identified ΔSUVpeak defined as ((during-treatment measure - baseline measure)/baseline measure) x 100%) LCCS defined as NO Lung Cancer Cause-specific disease 5 years post registration (Responders) OT defined as the ΔSUVpeak value corresponding to the maximum Youden index	Baseline to up to 5 years
FDG ΔMTV From Baseline to the During-treatment FDG PET/CT, to Predict Lung Cancer Cause-specific Survival and Optimal Threshold (ECOG-ACRIN)	FDG ΔMTV, as measured from Baseline to the During-treatment FDG PET/CT, will be assessed in its ability to predict Lung Cancer Cause-specific Survival (LCCS) and an Optimal Threshold (OT) for differentiating responders from non-responders will be identified FDG ΔMTV defined as ((during-treatment measure - baseline measure)/baseline measure) x 100%) LCCS defined as NO Lung Cancer Cause-specific disease 5 years post registration (Responders) OT defined as the ΔMTV value corresponding to the maximum Youden index	Baseline to up to 5 years
FMISO Hypoxic Tumor Volume (HV) @Baseline, to Predict Lung Cancer Cause-specific Survival and Optimal Threshold (ECOG-ACRIN)	FMISO Hypoxic tumor volume @baseline, will be assessed in its ability to predict Lung Cancer Cause-specific Survival (LCCS) and an Optimal Threshold (OT) for differentiating responders from non-responders will be identified HV defined as the number of pixels in the gross tumor volume with a tumor-to-blood pool ratio of > 1.2 in cc LCCS defined as NO Lung Cancer Cause-specific disease 5 years post registration (Responders) OT defined as the HV value corresponding to the maximum Youden index	Baseline to up to 5 years
FDG SUVmax @ Baseline FDG PET/CT, to Predict Local-Regional Progression-Free and Optimal Threshold (ECOG-ACRIN)	SUVmax, as measured at Baseline, will be assessed in its ability to predict Local-Regional Progression-Free(LRPF) and an Optimal Threshold (OT) for differentiating responders from non-responders will be identified LRPF defined as as NO progressive lung cancer within 1 cm from the planning target volume.or Progressive disease in any of the 14 nodal stations beyond 1cm 2 Years from regitration (Responders) OT defined as the SUVmax value corresponding to the maximum Youden index	Baseline to up to 5 years
FDG ΔSUVmax From Baseline to the During-treatment FDG PET/CT, to Predict Local-Regional Progression-Free and Optimal Threshold (ECOG-ACRIN)	FDG ΔSUVmax, as measured from Baseline to the During-treatment FDG PET/CT, will be assessed in its ability to predict Local-Regional Progression-Free (LRPF) and an Optimal Threshold (OT) for differentiating responders from non-responders will be identified ΔSUVmax defined as ((during-treatment measure - baseline measure)/baseline measure) x 100%) LRPF defined as as NO progressive lung cancer within 1 cm from the planning target volume.or Progressive disease in any of the 14 nodal stations beyond 1cm 2 Years from regitration (Responders) OT defined as the ΔSUVmax value corresponding to the maximum Youden index	Baseline to up to 5 years
FDG ΔSUVpeak From Baseline to the During-treatment FDG PET/CT, to Predict Local-Regional Progression-Free and Optimal Threshold (ECOG-ACRIN)	FDG ΔSUVpeak, as measured from Baseline to the During-treatment FDG PET/CT, will be assessed in its ability to predict Local-Regional Progression-Free (LRPF) and an Optimal Threshold (OT) for differentiating responders from non-responders will be identified ΔSUVpeak defined as ((during-treatment measure - baseline measure)/baseline measure) x 100%) LRPF defined as as NO progressive lung cancer within 1 cm from the planning target volume.or Progressive disease in any of the 14 nodal stations beyond 1cm 2 Years from regitration (Responders) OT defined as the ΔSUVpeak value corresponding to the maximum Youden index	Baseline to up to 5 years
FDG ΔMTV From Baseline to the During-treatment FDG PET/CT, to Predict Local-Regional Progression-Free and Optimal Threshold (ECOG-ACRIN)	FDG ΔMTV, as measured from Baseline to the During-treatment FDG PET/CT, will be assessed in its ability to predict Local-Regional Progression-Free (LRPF) and an Optimal Threshold (OT) for differentiating responders from non-responders will be identified FDG ΔMTV defined as ((during-treatment measure - baseline measure)/baseline measure) x 100%) LRPF defined as as NO progressive lung cancer within 1 cm from the planning target volume.or Progressive disease in any of the 14 nodal stations beyond 1cm 2 Years from regitration (Responders) OT defined as the ΔMTV value corresponding to the maximum Youden index	Baseline to up to 5 years
FMISO Hypoxic Tumor Volume @Baseline, to Predict Local-Regional Progression-Free and Optimal Threshold (ECOG-ACRIN)	FMISO Hypoxic tumor volume (HV) @baseline, will be assessed in its ability to predict Local-Regional Progression-Free (LRPF) and an Optimal Threshold (OT) for differentiating responders from non-responders will be identified HV defined as the number of pixels in the grLRPFs tumor volume with a tumor-to-blood pool ratio of > 1.2 in cc LRPF defined as as NO progressive lung cancer within 1 cm from the planning target volume.or Progressive disease in any of the 14 nodal stations beyond 1cm 2 Years from regitration (Responders) OT defined as the HV value corresponding to the maximum Youden index	Baseline to up to 5 years

Other Outcome Measures

Outcome Measure	Time Frame
Quantify Relationship Between Biomarkers and Grade 2+ Radiation-induced Lung Toxicity [RILT] (NRG)	Randomization to last follow-up.
Quantify Relationship Between Biomarkers and Two-year Local-regional Progression-free (LRPF) Survival (NRG)	From randomization to last follow-up: weekly during treatment, then 1, 3, 6, 9, 12, 18, 24, 30, 36, 48, and 60 months after end of protocol treatment, then annually. Maximum follow-up at time of reporting was 7.3 years.

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Collaborators: NRG Oncology
• Investigators: Principal Investigator: Feng-Ming (Spring) P Kong, NRG Oncology

Publications and helpful links

General Publications

• Kong FS, Hu C, Pryma DA, Duan F, Matuszak M, Xiao Y, Ten Haken R, Siegel MJ, Hanna L, Curran WJ, Dunphy M, Gelblum D, Piert M, Jolly S, Robinson CG, Quon A, Loo BW, Srinivas S, Videtic GM, Faria SL, Ferguson C, Dunlap NE, Kundapur V, Paulus R, Siegel BA, Bradley JD, Machtay M. Primary Results of NRG-RTOG1106/ECOG-ACRIN 6697: A Randomized Phase II Trial of Individualized Adaptive (chemo)Radiotherapy Using Midtreatment 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Stage III Non-Small Cell Lung Cancer. J Clin Oncol. 2024 Nov 20;42(33):3935-3946. doi: 10.1200/JCO.24.00022. Epub 2024 Oct 4.

Study record dates

Study Major Dates

• Study Start (Actual): February 22, 2012
• Primary Completion (Actual): August 17, 2020
• Study Completion (Actual): May 20, 2022

Study Registration Dates

• First Submitted: January 5, 2012
• First Submitted That Met QC Criteria: January 5, 2012
• First Posted (Estimated): January 10, 2012

Study Record Updates

• Last Update Posted (Actual): April 21, 2026
• Last Update Submitted That Met QC Criteria: April 7, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Organic Chemicals; Investigative Techniques; Hydrocarbons; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Carbohydrates; Physical Phenomena; Coordination Complexes; Taxoids; Cyclodecanes; Diterpenes; Health Care Economics and Organizations; Chemistry Techniques, Analytical; Spectrum Analysis; Deoxyglucose; Deoxy Sugars; Economics; Fluorodeoxyglucose F18; Carboplatin; Paclitaxel; Radiation; Magnetic Resonance Spectroscopy; Taxes; fluoromisonidazole
• Other Study ID Numbers: NCI-2012-00107 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U10CA180868 (U.S. NIH Grant/Contract); U10CA021661 (U.S. NIH Grant/Contract); CDR0000721619; RTOG-1106 (Other Identifier: CTEP); ACRIN-6697 (Other Identifier: ACRIN)