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)
IRB RTOG 1106
Hospital Fairview, Hillcrest, Independence, Main Campus, Strongsville, Wooster
- RTOG: To determine whether tumor dose can be escalated to improve the LRPF rate at 2 years when an individualized adaptive radiation treatment (RT) plan is applied by the use of a FDG-PET/CT scan acquired during the course of fractionated RT in patients with inoperable or unresectable stage III NSCLC;
- ACRIN: To determine whether the relative change in SUVpeak from the baseline to the during-treatment FDG-PET/CT, defined as (during-treatment SUVpeak � baseline SUVpeak)/baseline SUVpeak x 100%, can predict the LRPF with a 2-year follow up.
- To determine whether an individualized dose escalation improves overall survival (OS), progression-free survival (PFS), lung cancer cause-specific survival, and delays time to localregional progression compared to a conventional RT plan;
- To compare the rate of severe (grade 3+ CTCAE, v. 4) radiation-induced lung toxicity (RILT), as defined below:
- Severe RILT (pneumonitis)
- Severe cough, unresponsive to narcotic antitussive agent and /or dyspnea at rest, with radiographic evidence of acute pneumonitis, without evidence of infection, tumor progression or other etiologies, and requiring oxygen (intermittent or continuous) for treatment
- Radiation pneumonitis causes respiratory insufficiency, requiring assisted ventilation
- Radiation pneumonitis directly contributes to the cause of the death
- Severe RILT (clinical fibrosis)
- Radiographic evidence of radiation fibrosis causing dyspnea at rest, interfering with activities of daily living, without evidence of infection, tumor progression or other etiologies, and home oxygen indicated
- Radiation fibrosis causes respiratory insufficiency, requiring assisted ventilation
- Radiation fibrosis directly contributes to the cause of the death
- Severe RILT (pneumonitis)
- 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.
- To evaluate the association of baseline FMISO uptake (tumor-to-blood pool ratio) with LRPF (i.e. the assessment of using baseline FMISO-PET uptake as a prognostic marker);
- 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 depending on the assigned treatment. The aim is to assess if these uptake parameters can be useful in guiding therapies, i.e. predictive markers;
- To determine if other PET imaging uptake parameters (SUVpeak during-treatment for FDG-PET, maximum SUV, or relative change of maximum SUVs from pre- to during-treatment FDGPET/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, and lung cancer cause-specific (LCS) survival as well as to explore the optimal threshold for differentiating responders from non-responders.
- 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 and survival better than a current model using clinical factors and radiation dose as well as imaging factors;
- To determine/validate whether a model of combining mean lung dose (MLD), transforming growth factor beta1 (TGFβ1) and IL8 will improve the predictive accuracy for clinical significant RILT better comparing to the current model of using MLD alone;
- 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, PFS, OS, and pattern of failure and treatment-related adverse events, such as radiation pneumonitis, esophagitis, and pericardial effusion.
- 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 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 RT is planned.
- Appropriate stage for protocol entry, including no distant metastases, based upon the following minimum diagnostic workup:
- 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 thebrain within 6 weeks prior to registration;/li>
- Pulmonary function tests, including DLCO, within 6 weeks prior to registration; patients must have FEV1 ≥ 1.2 Liter or ≥ 50% predicted without bronchodilator;
- Zubrod Performance Status 0-1 within 2 weeks prior to registration;
- Age ≥ 18;
- Able to tolerate PET/CT imaging required to be performed at an ACR Imaging Core Lab qualified facility;
- CBC/differential obtained within 2 weeks prior to registration on study, with adequate bone marrow function defined as follows:
- Absolute neutrophil count (ANC) ≥ 1,500 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 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.
- 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 CDC definition; note, however, that 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.
- 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;
- For FMISO-PET/CT: patient is unable to undergo this imaging;
- Patients with T4 disease with radiographic evidence of massage invasion of a large pulmonary artery and tumor causing significant narrowing and destruction of that artery are excluded.