Study of Positron Emission Tomography and Computed Tomography in Guiding Radiation Therapy in Patients With Stage III Non-small Cell Lung Cancer

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.

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