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

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.

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.

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.

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.

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.

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.

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)

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

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

FDG SUVmax as measured at baseline PET imaging will be assessed in its ability to predict Overall Survival (OS) at year 5.

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.

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.

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

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

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

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

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

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

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

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

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

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

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

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

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