Gregory M.M. Videtic

Stereotactic Body Radiation Therapy for Inoperable Early Stage Lung Cancer

CONTEXT Patients with early stage but medically inoperable lung cancer have a poor rate of primary tumor control (30%-40%) and a high rate of mortality (3-year survival, 20%-35%) with current management. OBJECTIVE To evaluate the toxicity and efficacy of stereotactic body radiation therapy in a high-risk population of patients with early stage but medically inoperable lung cancer. DESIGN, SETTING, AND PATIENTS Phase 2 North American multicenter study of patients aged 18 years or older with biopsy-proven peripheral T1-T2N0M0 non-small cell tumors (measuring <5 cm in diameter) and medical conditions precluding surgical treatment. The prescription dose was 18 Gy per fraction x 3 fractions (54 Gy total) with entire treatment lasting between 1(1/2) and 2 weeks. The study opened May 26, 2004, and closed October 13, 2006; data were analyzed through August 31, 2009. MAIN OUTCOME MEASURES The primary end point was 2-year actuarial primary tumor control; secondary end points were disease-free survival (ie, primary tumor, involved lobe, regional, and disseminated recurrence), treatment-related toxicity, and overall survival. RESULTS A total of 59 patients accrued, of which 55 were evaluable (44 patients with T1 tumors and 11 patients with T2 tumors) with a median follow-up of 34.4 months (range, 4.8-49.9 months). Only 1 patient had a primary tumor failure; the estimated 3-year primary tumor control rate was 97.6% (95% confidence interval [CI], 84.3%-99.7%). Three patients had recurrence within the involved lobe; the 3-year primary tumor and involved lobe (local) control rate was 90.6% (95% CI, 76.0%-96.5%). Two patients experienced regional failure; the local-regional control rate was 87.2% (95% CI, 71.0%-94.7%). Eleven patients experienced disseminated recurrence; the 3-year rate of disseminated failure was 22.1% (95% CI, 12.3%-37.8%). The rates for disease-free survival and overall survival at 3 years were 48.3% (95% CI, 34.4%-60.8%) and 55.8% (95% CI, 41.6%-67.9%), respectively. The median overall survival was 48.1 months (95% CI, 29.6 months to not reached). Protocol-specified treatment-related grade 3 adverse events were reported in 7 patients (12.7%; 95% CI, 9.6%-15.8%); grade 4 adverse events were reported in 2 patients (3.6%; 95% CI, 2.7%-4.5%). No grade 5 adverse events were reported. CONCLUSION Patients with inoperable non-small cell lung cancer who received stereotactic body radiation therapy had a survival rate of 55.8% at 3 years, high rates of local tumor control, and moderate treatment-related morbidity.

Primary analysis of a phase II randomized trial Radiation Therapy Oncology Group (RTOG) 0212: impact of different total doses and schedules of prophylactic cranial irradiation on chronic neurotoxicity and quality of life for patients with limited-disease small-cell lung cancer.

PURPOSE To determine the effect of dose and fractionation schedule of prophylactic cranial irradiation (PCI) on the incidence of chronic neurotoxicity (CNt) and changes in quality of life for selected patients with limited-disease small-cell lung cancer (LD SCLC). METHODS AND MATERIALS Patients with LD SCLC who achieved a complete response after chemotherapy and thoracic irradiation were eligible for randomization to undergo PCI to a total dose of 25 Gy in 10 daily fractions (Arm 1) vs. the experimental cohort of 36 Gy. Those receiving 36 Gy underwent a secondary randomization between daily 18 fractions (Arm 2) and twice-daily 24 fractions (Arm 3). Enrolled patients participated in baseline and follow-up neuropsychological test batteries along with quality-of-life assessments. RESULTS A total of 265 patients were accrued, with 131 in Arm 1, 67 in Arm 2, and 66 in Arm 3 being eligible. There are 112 patients (42.2%) alive with 25.3 months of median follow-up. There were no significant baseline differences among groups regarding quality-of-life measures and one of the neuropsychological tests, namely the Hopkins Verbal Learning Test. However, at 12 months after PCI there was a significant increase in the occurrence of CNt in the 36-Gy cohort (p=0.02). Logistic regression analysis revealed increasing age to be the most significant predictor of CNt (p=0.005). CONCLUSIONS Because of the increased risk of developing CNt in study patients with 36 Gy, a total PCI dose of 25 Gy remains the standard of care for patients with LD SCLC attaining a complete response to initial chemoradiation.

Palliative thoracic radiotherapy in lung cancer: An American Society for Radiation Oncology evidence-based clinical practice guideline

Purpose To provide guidance to physicians and patients with regard to the use of external beam radiotherapy, endobronchial brachytherapy, and concurrent chemotherapy in the setting of palliative thoracic treatment for lung cancer, based on available evidence complemented by expert opinion. Methods and Materials A Task Force authorized by the American Society for Radiation Oncology (ASTRO) Board of Directors synthesized and assessed evidence from 3 systematic reviews on the following topics: (1) dose fractionation in thoracic external beam radiotherapy (EBRT); (2) clinical utility of initial and salvage endobronchial brachytherapy (EBB); and (3) use of concurrent chemotherapy (CC) with palliative thoracic radiotherapy. Practice guideline recommendations were produced and are contained herein. Results Studies suggest that higher dose/fractionation palliative EBRT regimens (eg, 30 Gy/10 fraction equivalent or greater) are associated with modest improvements in survival and total symptom score, particularly in patients with good performance status. As these improvements are associated with an increase in esophageal toxicity, various shorter EBRT dose/fractionation schedules (eg, 20 Gy in 5 fractions, 17 Gy in 2 weekly fractions, 10 Gy in 1 fraction), which provide good symptomatic relief with fewer side effects, can be used for patients requesting a shorter treatment course and/or in those with a poor performance status. No defined role for EBB in the routine initial palliative treatment of chest disease has been demonstrated; however, EBB can be a reasonable option for the palliation of endobronchial lesions causing obstructive symptomatology including lung collapse, or for hemoptysis after EBRT failure. The integration of concurrent chemotherapy with palliative intent/fractionated radiotherapy is not currently supported by the medical literature. Conclusion This Guideline is intended to serve as a guide for the use of EBRT, EBB, and CC in thoracic palliation of lung cancer outside the clinical trial setting. Further prospective clinical investigations with relevant palliative endpoints into the respective roles of EBB and CC/targeted therapy in the thoracic palliation of lung cancer are warranted, given the current state of the medical literature in these areas.

A Comparison of Two Stereotactic Body Radiation Fractionation Schedules for Medically Inoperable Stage I Non-small Cell Lung Cancer: The Cleveland Clinic Experience

Purpose: To assess the impact of fractionation upon tumor control and toxicity in medically inoperable early stage lung cancer patients treated with stereotactic body radiotherapy. Methods: We reviewed 94 consecutive stereotactic body radiotherapy treatments (86 patients) with medically inoperable stage I non-small cell lung cancer receiving either 50 Gy in five fractions (n = 56) or 60 Gy in three fractions (n = 38) from October 2003 to August 2007. Institutional practice was 10 Gy × 5 before March 1, 2006, when it changed to 20 Gy × 3 to conform to Radiation Therapy Oncology Group 0236 unless otherwise dictated clinically. Results: Median age was 73 years and median Karnofsky performance status 80. A total of 69 lesions were T1, 24 were T2 lung cancer. Median follow-up was 15.3 months. For the 50- and 60-Gy cohorts at 1 year, local control was 97.3% versus 100%, nodal failure 7.3% versus 3.4%, distant metastasis rate 21.8% versus 29.5%, and overall survival 83.1% versus 76.9% (p = 0.68, 0.54, 0.56, and 0.54, respectively). There was no difference in overall survival for patients with histologic (n = 61) compared with radiographic (n = 33) diagnosis. There was no impact of fractionation in the subset of T2 tumors. We observed two cases (2.2%) of clinical grade 2 pneumonitis. Mild late chest wall toxicity (grade 1 or 2) was seen in nine patients (10%) at a median of 8.4 months after treatment and was more common in the 60-Gy group (7 of 38 [18%] versus 2 of 56 [4%], p = 0.028). Conclusions: Local control, overall survival, nodal failure, and distant failure were not affected by fractionation. Chest wall toxicity was more common with 60-Gy group.

Comprehensive Analysis of Pulmonary Function Test (PFT) Changes After Stereotactic Body Radiotherapy (SBRT) for Stage I Lung Cancer in Medically Inoperable Patients

Background: To assess for variables predicting pulmonary function test (PFT) changes after stereotactic body radiotherapy (SBRT) for medically inoperable stage I lung cancer. Methods: We reviewed 92 consecutive patients undergoing SBRT for stage I lung cancer between February 2004 and August 2007. A total of 102 lesions were treated using prescriptions of 20 Gy × 3 (n = 40), 10 Gy × 5 (n = 56), and 5 Gy × 10 (n = 6). Institutional practice was 10 Gy × 5 before March 1, 2006 before changing to 20 Gy × 3 to conform to RTOG 0236 unless otherwise dictated clinically. Results: Median pretreatment forced expiratory volume at 1 second (FEV1) was 1.21 liter (50% of predicted) and median diffusion capacity to carbon monoxide (DLCO) was 56.5. There was no significant overall change in PFTs after SBRT. Individual patients experienced both substantial improvements and declines (10% declined at least 14% predicted FEV1% and 19% predicted DLCO). The mean change in FEV1 was −0.05 liter (range, −0.98 to +1.29 liter; p = 0.22) representing −1.88% predicted baseline FEV1 (range, −33 to + 43%; p = 0.62). DLCO declined 2.59% of predicted (range, −37 to +33%; p = 0.27). Conformality index, V5 and V10 were associated with individual patient changes in FEV1% (p = 0.033, p = 0.0036, p = 0.025, respectively), however, correlations were small and overall treatment dose did not predict for changes (p = 0.95). There was no significant difference in FEV1 (p = 0.55) or FEV1% (p = 0.37) changes for central versus peripheral locations. No factors predicted for individual changes in DLCO. Patients with FEV1% below the median of the study population had significantly longer overall survival (p = 0.0065). Although patients dying of cardiac disease died earlier than those dying of other causes, FEV1% below median was not associated with a lower risk of dying of cardiac disease or with lower Charlson comorbidity index. Conclusions: (1) SBRT was well tolerated and PFT changes were minimal. (2) Central lesions were safely treated with 50 Gy.

Intensity-Modulated Radiotherapy-Based Stereotactic Body Radiotherapy for Medically Inoperable Early-Stage Lung Cancer: Excellent Local Control

PURPOSE To validate the use of stereotactic body radiotherapy (SBRT) using intensity-modulated radiotherapy (IMRT) beams for medically inoperable Stage I lung cancer. METHODS AND MATERIALS From February 2004 to November 2006, a total of 26 patients with 28 lesions received SBRT using a Novalis/BrainLAB system. Immobilization involved a Bodyfix vacuum cushion. A weighted abdominal belt limited respiratory excursion. Computed tomographic simulation images were acquired at rest, full inhalation, and full exhalation and were merged to generate an internal gross tumor volume (ITV). Dose was prescribed to cover the planning target volume (PTV), defined as PTV = ITV + 3-5 mm set-up margin. Heterogeneity corrections were used. Delivery of 50 Gy in five sequential fractions typically used seven nonopposing, noncoplanar beams. Image-guided target verification was provided by BrainLAB-ExacTrac. RESULTS Among the 26 patients, the mean age was 74 years (range, 49-88 years). Of the patients, 50% were male and 50% female. The median Karnofsky performance status was 70 (range, 40-100). The median follow-up was 30.9 months (range, 10.4-51.4 months). Tissue diagnosis was contraindicated in seven patients (26.9%). There were 22 T1 (78.6%) and six T2 (21.4%) tumors. The median conformality index was 1.38 (range, 1.12-1.8). The median heterogeneity index was 1.08 (range, 1.04-1.2). One patient (3.6%) developed acute Grade 3 dyspnea and one patient developed late Grade 2 chest wall pain. Actuarial local control and overall survival at 3 years were 94.4% and 52%, respectively. CONCLUSIONS Use of IMRT-based delivery of SBRT using restriction of tumor motion in medically inoperable lung cancer demonstrates excellent local control and favorable survival.

Prediction of Chest Wall Toxicity From Lung Stereotactic Body Radiotherapy (SBRT)

PURPOSE To determine patient, tumor, and treatment factors related to the development of late chest wall toxicity after lung stereotactic body radiotherapy (SBRT). METHODS AND MATERIALS We reviewed a registry of 134 patients treated with lung SBRT to 60 Gy in 3 fractions who had greater than 1 year of clinical follow-up and no history of multiple treatments to the same lobe (n = 48). Patients were treated as per Radiation Therapy Oncology Group Protocol 0236 without specific chest wall avoidance criteria. The chest wall was retrospectively contoured. Thirty-two lesions measured less than 3 cm, and sixteen measured 3 to 5 cm. The median planning target volume was 29 cm(3). RESULTS With a median follow-up of 18.8 months, 10 patients had late symptomatic chest wall toxicity (4 Grade 1 and 6 Grade 2) at a median of 8.8 months after SBRT. No patient characteristics (age, diabetes, hypertension, peripheral vascular disease, or body mass index) were predictive for toxicity, whereas there was a trend for continued smoking (p = 0.066; odds ratio [OR], 4.4). Greatest single tumor dimension (p = 0.047; OR, 2.63) and planning target volume (p = 0.040; OR, 1.04) were correlated with toxicity, whereas distance from tumor edge to chest wall and gross tumor volume did not reach statistical significance. Volumes of chest wall receiving 30 Gy (V30) through 70 Gy (V70) were all highly significant, although this correlation weakened for V65 and V70 and maximum chest wall point dose only trended to significance (p = 0.06). On multivariate analysis, tumor volume was no longer correlated with toxicity and only V30 through V60 remained statistically significant. CONCLUSIONS Tumor size and chest wall dosimetry are correlated to late chest wall toxicity. Only chest wall V30 through V60 remained significant on multivariate analysis. Restricting V30 to 30 cm(3) or less and V60 to 3 cm(3) or less should result in a 10% to 15% risk of late chest wall toxicity or lower.

Report From the International Atomic Energy Agency (IAEA) Consultants' Meeting on Elective Nodal Irradiation in Lung Cancer: Small-Cell Lung Cancer (SCLC)

Thoracic radiotherapy (RT) is an integral part of the management of small-cell lung cancer (SCLC) because its administration provides a survival benefit in patients with limited-stage disease. However, there are many areas of controversy with respect to the delivery of curative RT, and these include definition of the target to be irradiated. A current area of concern is defining what the RT portal must encompass with respect to the mediastinal lymph nodes; that is, whether one should electively treat all mediastinal nodes, or selectively include those with some clinical risk for harboring disease, or perhaps omit elective nodal irradiation altogether. The purpose of the present report is therefore to address the concepts underlying elective or selective nodal irradiation as it applies to SCLC, looking at clinical, imaging, and RT reports to help define the parameters appropriate to treating individual patients.

A Randomized Phase 2 Study Comparing 2 Stereotactic Body Radiation Therapy Schedules for Medically Inoperable Patients With Stage I Peripheral Non-Small Cell Lung Cancer: NRG Oncology RTOG 0915 (NCCTG N0927)

PURPOSE To compare 2 stereotactic body radiation therapy (SBRT) schedules for medically inoperable early-stage lung cancer to determine which produces the lowest rate of grade ≥3 protocol-specified adverse events (psAEs) at 1 year. METHODS AND MATERIALS Patients with biopsy-proven peripheral (≥2 cm from the central bronchial tree) T1 or T2, N0 (clinically node negative by positron emission tomography), M0 tumors were eligible. Patients were randomized to receive either 34 Gy in 1 fraction (arm 1) or 48 Gy in 4 consecutive daily fractions (arm 2). Rigorous central accreditation and quality assurance confirmed treatment per protocol guidelines. This study was designed to detect a psAEs rate >17% at a 10% significance level (1-sided) and 90% power. Secondary endpoints included rates of primary tumor control (PC), overall survival (OS), and disease-free survival (DFS) at 1 year. Designating the better of the 2 regimens was based on prespecified rules of psAEs and PC for each arm. RESULTS Ninety-four patients were accrued between September 2009 and March 2011. The median follow-up time was 30.2 months. Of 84 analyzable patients, 39 were in arm 1 and 45 in arm 2. Patient and tumor characteristics were balanced between arms. Four (10.3%) patients on arm 1 (95% confidence interval [CI] 2.9%-24.2%) and 6 (13.3%) patients on arm 2 (95% CI 5.1%-26.8%) experienced psAEs. The 2-year OS rate was 61.3% (95% CI 44.2%-74.6%) for arm 1 patients and 77.7% (95% CI 62.5%-87.3%) for arm 2. The 2-year DFS was 56.4% (95% CI 39.6%-70.2%) for arm 1 and 71.1% (95% CI 55.5%-82.1%) for arm 2. The 1-year PC rate was 97.0% (95% CI 84.2%-99.9%) for arm 1 and 92.7% (95% CI 80.1%-98.5%) for arm 2. CONCLUSIONS 34 Gy in 1 fraction met the prespecified criteria and, of the 2 schedules, warrants further clinical research.

No Clinically Significant Changes in Pulmonary Function Following Stereotactic Body Radiation Therapy for Early- Stage Peripheral Non-Small Cell Lung Cancer: An Analysis of RTOG 0236

PURPOSE To investigate pulmonary function test (PFT) results and arterial blood gas changes (complete PFT) following stereotactic body radiation therapy (SBRT) and to see whether baseline PFT correlates with lung toxicity and overall survival in medically inoperable patients receiving SBRT for early stage, peripheral, non-small cell lung cancer (NSCLC). METHODS AND MATERIALS During the 2-year follow-up, PFT data were collected for patients with T1-T2N0M0 peripheral NSCLC who received effectively 18 Gy × 3 in a phase 2 North American multicenter study (Radiation Therapy Oncology Group [RTOG] protocol 0236). Pulmonary toxicity was graded by using the RTOG SBRT pulmonary toxicity scale. Paired Wilcoxon signed rank test, logistic regression model, and Kaplan-Meier method were used for statistical analysis. RESULTS At 2 years, mean percentage predicted forced expiratory volume in the first second and diffusing capacity for carbon monoxide declines were 5.8% and 6.3%, respectively, with minimal changes in arterial blood gases and no significant decline in oxygen saturation. Baseline PFT was not predictive of any pulmonary toxicity following SBRT. Whole-lung V5 (the percentage of normal lung tissue receiving 5 Gy), V10, V20, and mean dose to the whole lung were almost identical between patients who developed pneumonitis and patients who were pneumonitis-free. Poor baseline PFT did not predict decreased overall survival. Patients with poor baseline PFT as the reason for medical inoperability had higher median and overall survival rates than patients with normal baseline PFT values but with cardiac morbidity. CONCLUSIONS Poor baseline PFT did not appear to predict pulmonary toxicity or decreased overall survival after SBRT in this medically inoperable population. Poor baseline PFT alone should not be used to exclude patients with early stage lung cancer from treatment with SBRT.