Clinical trial NCT01507428: Study of Positron Emission Tomography and Computed Tomography in Guiding Radiation Therapy in Patients With Stage III Non-small Cell Lung Cancer
Official title: 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)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Stage III Lung Non-Small Cell Cancer AJCC v7
Stage IIIA Lung Non-Small Cell Cancer AJCC v7
Stage IIIB Lung Non-Small Cell Cancer AJCC v7
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
Collaborators: name: NRG Oncology
First posted: 2012-01-10
Enrollment: 138
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Local-regional, progression-free (LRPF) rate (National Surgical Adjuvant Breast and Bowel Project [NSABP], Radiation Therapy Oncology Group [RTOG], Gynecologic Oncology Group [GOG] [NRG])
timeFrame: 2 years
measure: Relative change in standard uptake volume (SUV) peak from the baseline to the during-treatment fludeoxyglucose F 18 (FDG)-positron emission tomography (PET)/computed tomography (CT) to LRPF (ECOG-ACRIN)
timeFrame: Baseline to 2 years
Secondary outcomes:
measure: Time to local-regional progression (NRG)
timeFrame: Interval from registration to date of local or regional progression, assessed up to 5 years
measure: Overall survival (OS) (NRG)
timeFrame: Interval from registration to the date of death or censored at the date of data collection, assessed up to 5 years
measure: Progression free survival (PFS) (NRG)
timeFrame: Interval from the date of registration to the date of tumor progression locally, regionally, distantly, or death, whichever occurs first, or censored at the last date of data collection, assessed up to 5 years
measure: Lung cancer cause-specific survival (NRG)
timeFrame: Interval from the date of registration to the date of death directly from lung cancer, or censored at the last date of data collection if still alive, assessed up to 5 years
measure: Radiation-induced lung toxicity (NRG)
timeFrame: Up to 5 years
measure: Incidence of grade 3+ esophagitis or cardiac adverse events related to chemoradiation between a conventional RT plan and a PET/CT-guided adaptive RT plan, as measured by Common Terminology Criteria for Adverse Events, version 4 and 5 (NRG)
timeFrame: Up to 5 years
measure: Baseline 18F-fluoromisonidazole (FMISO) uptake (tumor-to-blood pool ratio) association with LRPF (i.e. the assessment of using baseline FMISO-PET uptake as a prognostic marker) (ECOG-ACRIN)
timeFrame: Baseline
measure: Relative change in SUV peak from the baseline to the during-treatment FDG PET/CT and/or the baseline FMISO uptake (tumor-to-blood pool ratio) prediction of the differential benefit of the adaptive therapy (ECOG-ACRIN)
timeFrame: Baseline to up to 5 years
measure: Change of peak SUVs for FDG from pre- to during-treatment (ECOG-ACRIN)
timeFrame: Baseline to up to 5 years
measure: Max SUV or change of max SUVs for FDG from pre- to during-treatment (ECOG-ACRIN)
timeFrame: Baseline to up to 5 years
measure: Change in metabolic tumor volume (ECOG-ACRIN)
timeFrame: Baseline to up to 5 years
measure: FMISO total hypoxic volume (ECOG-ACRIN)
timeFrame: Up to 5 years
measure: FMISO tumor-to-blood pool ratio (ECOG-ACRIN)
timeFrame: Up to 5 years
measure: Prediction of OS, LRPF, and lung cancer cause-specific survival (ECOG-ACRIN)
timeFrame: Up to 5 years
measure: Optimal threshold for differentiating responders from non-responders (ECOG-ACRIN)
timeFrame: Up to 5 years
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford Cancer Institute Palo Alto
state: California
city: Augusta
country: United States
facility: Augusta University Medical Center
state: Georgia
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University/Melvin and Bren Simon Cancer Center
state: Indiana
city: Louisville
country: United States
facility: The James Graham Brown Cancer Center at University of Louisville
state: Kentucky
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Kansas City
country: United States
facility: Saint Luke's Hospital of Kansas City
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Basking Ridge
country: United States
facility: Memorial Sloan Kettering Basking Ridge
state: New Jersey
city: Commack
country: United States
facility: Memorial Sloan Kettering Commack
state: New York
city: Harrison
country: United States
facility: Memorial Sloan Kettering Westchester
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Sleepy Hollow
country: United States
facility: Memorial Sloan Kettering Sleepy Hollow
state: New York
city: Uniondale
country: United States
facility: Memorial Sloan Kettering Nassau
state: New York
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Cancer Center/Fairview Hospital
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Independence
country: United States
facility: Cleveland Clinic Cancer Center Independence
state: Ohio
city: Mayfield Heights
country: United States
facility: Hillcrest Hospital Cancer Center
state: Ohio
city: Strongsville
country: United States
facility: Cleveland Clinic Cancer Center Strongsville
state: Ohio
city: Wooster
country: United States
facility: Cleveland Clinic Wooster Family Health and Surgery Center
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: West Reading
country: United States
facility: Reading Hospital
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Montreal
country: Canada
facility: McGill University Department of Oncology
state: Quebec
city: Saskatoon
country: Canada
facility: Saskatoon Cancer Centre
state: Saskatchewan
Study officials:
affiliation: NRG Oncology
name: Feng-Ming (Spring) P Kong
role: PRINCIPAL_INVESTIGATOR
References: