RTOG 0813: Seamless Phase I/II Study of Stereotactic Lung Radiotherapy (SBRT) for Early Stage, Centrally Located Non-Small Cell Lung Cancer (NSCLC) in Medically Inoperable Patients
The primary endpoint of the study is the maximal tolerated dose (MTD) of a SBRT schedule of 5
fractions, administered on alternate days, over 1(1/2) - 2 weeks, for stage I NSCLC tumors that are touching or within the zone of the proximal bronchial tree or are adjacent to mediastinal or pericardial pleura (as these are also dose-limiting organs for high dose SBRT).
Five fractions were chosen because this short, practical schedule is suitable for patients with comorbidities and/or patients traveling from a distance to an SBRT center, as well as being within the definition of SBRT as accepted by regulatory bodies; it has potential radio-biological advantages of the 3 fraction schedule as repair of sub-lethal damage occurs after each fraction. Thus, more repair and greater tolerance of normal structures would be expected, particularly in the penumbra region of the high dose with 5 rather than with 3 fractions
The MTD for this schedule will be assessed by the adverse events within the first 12 months following study entry. This was felt to be more clinically relevant than the classical 90 day toxicity, as the dose-limiting toxicity of SBRT to central thoracic structures may be acute (within a month of SBRT) but is more likely to be sub-acute (1-6 months post SBRT) and chronic (more than 6 months post SBRT). The starting RT dose for the study will be 10 Gy x 5 fractions every 2 days, over 1(1/2) - 2 weeks (total dose [TD] of 50 Gy). The subsequent dose levels will escalate dose by 0.5 Gy per fraction (i.e., a 2.5 Gy total dose) to a maximum dose of 12 Gy x 5 fractions (TD 60 Gy in 5 fractions). Several lower dose levels will be employed if unacceptable dose-limiting toxicity (DLT) is seen with the planned starting dose of 10 Gy. All treatment plans will have to respect the organ-at-risk doses.
• Pathologically (histologically or cytologically) proven diagnosis of non-small cell lung cancer (NSCLC);
• Stage T1-2, N0, M0 (AJCC Staging, 6th Ed.), tumor size ≤ 5 cm, prior to registration, based upon the following minimum diagnostic workup
• History/physical examination within 4 weeks prior to registration;
• Evaluation by an experienced thoracic cancer surgeon within 12 weeks prior to registration; the primary tumor must be deemed technically resectable by an experienced thoracic cancer clinician, with a reasonable possibility of obtaining a gross total resection with negative margins, defined as a potentially curative resection (PCR). However, the patient must have underlying physiological medical problems that would prohibit a PCR due to a low probability of tolerating general anesthesia, the operation, the post-operative recovery period, or the removal of adjacent functioning lung. These types of patients with severe underlying health problems are deemed “medically inoperable.” Standard justification for deeming a patient medically inoperable based on pulmonary function for surgical resection of NSCLC will include any of the following: Baseline FEV1 < 40% predicted, post-operative FEV1 < 30% predicted; severely reduced diffusion capacity; baseline hypoxemia and/or hypercapnia; exercise oxygen consumption < 50% predicted; severe pulmonary hypertension; diabetes mellitus with severe end organ damage; severe cerebral, cardiac, or peripheral vascular disease; or severe chronic heart disease.
• Imaging as follows:
o CT scan with contrast (unless medically contraindicated) within 8 weeks of registration.
The CT scan will include the entirety of both lungs, the mediastinum, liver and adrenal
glands; the primary tumor dimensions will be measured on CT. Note: Patients with
lesions that cannot be visualized by CT scan are not eligible for the study.
o Whole body positron emission tomography (PET) scan within 8 weeks of registration,
using FDG with adequate visualization of the primary tumor and draining lymph node basins in the hilar and mediastinal regions.
Patients with hilar or mediastinal lymph nodes ≤ 1 cm and no abnormal hilar or mediastinal uptake on PET will be considered N0. Mediastinal lymph node sampling by any technique is allowed but not required. Patients with > 1 cm hilar or mediastinal lymph nodes on CT or abnormal PET (including suspicious but nondiagnostic uptake) may still be eligible if directed tissue biopsies of all abnormally identified areas are negative for cancer.
• Zubrod Performance Status 0-2 within 4 weeks prior to registration;
• Age ≥ 18;
• Tumor within or touching the zone of the proximal bronchial tree, defined as a volume 2 cm in all directions around the proximal bronchial tree (carina, right and left main bronchi, right and
left upper lobe bronchi, intermedius bronchus, right middle lobe bronchus, lingular bronchus
right and left lower lobe bronchi). [See figure below] Tumors that are immediately adjacent to
mediastinal or pericardial pleura also are considered central tumors and are eligible for this
• Patients must have measurable disease.
• Pleural effusion, if present, must be deemed too small to tap under CT guidance and must not be evident on chest x-ray. Pleural effusion that appears on chest x-ray will be permitted only after thoracotomy or other invasive procedure(s).
• Negative serum or urine pregnancy test within 72 hours prior to registration for women of
• 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 (until at least 60 days following the last study treatment);
• Patients must provide study-specific informed consent prior to any protocol specified