K.L. Stephans

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.

Differential Distribution and Function of Hyperpolarization-Activated Channels in Sensory Neurons and Mechanosensitive Fibers

Sensory neurons express hyperpolarization-activated currents (IH) that differ in magnitude and kinetics within the populations. We investigated the structural basis for these differences and explored the functional role of the IH channels in sensory neurons isolated from rat nodose ganglia. Immunohistochemical studies demonstrated a differential distribution of hyperpolarization-activated cyclic nucleotide-gated (HCN) protein (HCN1, HCN2, HCN4) in sensory neurons and peripheral terminals. HCN2 and HCN4 immunoreactivity was present in all nodose neurons. In contrast, only 20% of the total population expressed HCN1 immunoreactivity. HCN1 did not colocalize with IB4 (a marker for C-type neurons), and only 15% of HCN1-positive neurons colocalized with immunoreactivity for the vanilloid receptor VR1, another protein associated primarily with C-type neurons. Therefore, most HCN1-containing neurons were A-type neurons. In further support, HCN1 was present in the mechanosensitive terminals of myelinated but not unmyelinated sensory fibers, whereas HCN2 and HCN4 were present in receptor terminals of both myelinated and unmyelinated fibers. In voltage-clamp studies, cell permeant cAMP analogs shifted the activation curve for IH to depolarized potentials in C-type neurons but not A-type neurons. In current-clamp recording, CsCl, which inhibits only IH in nodose neurons, hyperpolarized the resting membrane potential from –63 ± 1 to –73 ± 2 mV and nearly doubled the input resistance from 1.3 to 2.2 GΩ. In addition, action potentials were initiated at lower depolarizing current injections in the presence of CsCl. At the sensory receptor terminal, CsCl decreased the threshold pressure for initiation of mechanoreceptor discharge. Therefore, elimination of the IH increases excitability of both the soma and the peripheral sensory terminals.

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.

MAXIMUM STANDARDIZED UPTAKE VALUE FROM STAGING FDG-PET/CT DOES NOT PREDICT TREATMENT OUTCOME FOR EARLY-STAGE NON-SMALL-CELL LUNG CANCER TREATED WITH STEREOTACTIC BODY RADIOTHERAPY

PURPOSE To perform a retrospective review to determine whether maximum standardized uptake values (SUV(max)) from staging 2-deoxy-2- [(18)F] fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) studies are associated with outcomes for early-stage non-small-cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT). METHODS AND MATERIALS Seventy-two medically inoperable patients were treated between October 17, 2003 and August 17, 2007 with SBRT for T1-2N0M0 NSCLC. SBRT was administered as 60 Gy in 3 fractions, 50 Gy in 5 fractions, or 50 Gy in 10 fractions using abdominal compression and image-guided SBRT. Cox proportional hazards regression was performed to determine whether PET SUV(max) and other variables influenced outcomes: mediastinal failure (MF), distant metastases (DM), and overall survival (OS). RESULTS Biopsy was feasible in 49 patients (68.1%). Forty-nine patients had T1N0 disease, and 23 had T2N0 disease. Median SUV(max) was 6.55 (range, 1.5-21). Median follow-up was 16.9 months (range, 0.1-37.9 months). There were 3 local failures, 8 MF, 19 DM, and 30 deaths. Two-year local control, MF, DM, and OS rates were 94.0%, 10.4%, 30.1%, and 61.3%, respectively. In univariate analysis, PET/CT SUV(max), defined either as a continuous or dichotomous variable, did not predict for MF, DM, or OS. On multivariable analysis, the only predictors for overall survival were T1 stage (hazard ratio = 0.331 [95% confidence interval, 0.156-0.701], p = 0.0039) and smoking pack-year history (hazard ratio = 1.015 [95% confidence interval, 1.004-1.026], p = 0.0084). CONCLUSIONS Pretreatment PET SUV(max) did not predict for MF, DM, or OS in patients treated with SBRT for early-stage NSCLC.

Contemporary Update of a Multi-Institutional Predictive Nomogram for Salvage Radiotherapy After Radical Prostatectomy

PURPOSE We aimed to update a previously published, multi-institutional nomogram of outcomes for salvage radiotherapy (SRT) following radical prostatectomy (RP) for prostate cancer, including patients treated in the contemporary era. METHODS Individual data from node-negative patients with a detectable post-RP prostate-specific antigen (PSA) treated with SRT with or without concurrent androgen-deprivation therapy (ADT) were obtained from 10 academic institutions. Freedom from biochemical failure (FFBF) and distant metastases (DM) rates were estimated, and predictive nomograms were generated. RESULTS Overall, 2,460 patients with a median follow-up of 5 years were included; 599 patients (24%) had a Gleason score (GS) ≤ 6, 1,387 (56%) had a GS of 7, 244 (10%) had a GS of 8, and 230 (9%) had a GS of 9 to 10. There were 1,370 patients (56%) with extraprostatic extension (EPE), 452 (18%) with seminal vesicle invasion (SVI), 1,434 (58%) with positive surgical margins, and 390 (16%) who received ADT (median, 6 months). The median pre-SRT PSA was 0.5 ng/mL (interquartile range, 0.3 to 1.1). The 5-yr FFBF rate was 56% overall, 71% for those with a pre-SRT PSA level of 0.01 to 0.2 ng/mL (n = 441), 63% for those with a PSA of 0.21 to 0.50 ng/mL (n = 822), 54% for those with a PSA of 0.51 to 1.0 ng/mL (n = 533), 43% for those with a PSA of 1.01 to 2.0 ng/mL (n = 341), and 37% for those with a PSA > 2.0 ng/mL (n = 323); P < .001. On multivariable analysis, pre-SRT PSA, GS, EPE, SVI, surgical margins, ADT use, and SRT dose were associated with FFBF. Pre-SRT PSA, GS, SVI, surgical margins, and ADT use were associated with DM, whereas EPE and SRT dose were not. The nomogram concordance indices were 0.68 (FFBF) and 0.74 (DM). CONCLUSION Early SRT at low PSA levels after RP is associated with improved FFBF and DM rates. Contemporary nomograms can estimate individual patient outcomes after SRT in the modern era.

Multicenter results of stereotactic body radiotherapy (SBRT) for non-resectable primary liver tumors

Abstract Background. An excess of 100 000 individuals are diagnosed with primary liver tumors every year in USA but less than 20% of those patients are amenable to definitive surgical management due to advanced local disease or comorbidities. Local therapies to arrest tumor growth have limited response and have shown no improvement on patient survival. Stereotactic body radiotherapy (SBRT) has emerged as an alternative local ablative therapy. The purpose of this study was to evaluate the tumor response to SBRT in a combined multicenter database. Study design. Patients with advanced hepatocellular carcinoma (HCC, n = 21) or intrahepatic cholangiocarcinoma (ICC, n = 11) treated with SBRT from four Academic Medical Centers were entered into a common database. Statistical analyses were performed for freedom from local progression (FFLP) and patient survival. Results. The overall FFLP for advanced HCC was 63% at a median follow-up of 12.9 months. Median tumor volume decreased from 334.2 to 135 cm3 (p < 0.004). The median time to local progression was 6.3 months. The 1- and 2-years overall survival rates were 87% and 55%, respectively. Patients with ICC had an overall FFLP of 55.5% at a median follow-up of 7.8 months. The median time to local progression was 4.2 months and the six-month and one-year overall survival rates were 75% and 45%, respectively. The incidence of grade 1–2 toxicities, mostly nausea and fatigue, was 39.5%. Grade 3 and 4 toxicities were present in two and one patients, respectively. Conclusion. Higher rates of FFLP were achieved by SBRT in the treatment of primary liver malignancies with low toxicity.

Predicting chest wall pain from lung stereotactic body radiotherapy for different fractionation schemes.

PURPOSE Recent studies with two fractionation schemes predicted that the volume of chest wall receiving >30 Gy (V30) correlated with chest wall pain after stereotactic body radiation therapy (SBRT) to the lung. This study developed a predictive model of chest wall pain incorporating radiobiologic effects, using clinical data from four distinct SBRT fractionation schemes. METHODS AND MATERIALS 102 SBRT patients were treated with four different fractionations: 60 Gy in three fractions, 50 Gy in five fractions, 48 Gy in four fractions, and 50 Gy in 10 fractions. To account for radiobiologic effects, a modified equivalent uniform dose (mEUD) model calculated the dose to the chest wall with volume weighting. For comparison, V30 and maximum point dose were also reported. Using univariable logistic regression, the association of radiation dose and clinical variables with chest wall pain was assessed by uncertainty coefficient (U) and C statistic (C) of receiver operator curve. The significant associations from the univariable model were verified with a multivariable model. RESULTS 106 lesions in 102 patients with a mean age of 72 were included, with a mean of 25.5 (range, 12-55) months of follow-up. Twenty patients reported chest wall pain at a mean time of 8.1 (95% confidence interval, 6.3-9.8) months after treatment. The mEUD models, V30, and maximum point dose were significant predictors of chest wall pain (p < 0.0005). mEUD improved prediction of chest wall pain compared with V30 (C = 0.79 vs. 0.77 and U = 0.16 vs. 0.11). The mEUD with moderate weighting (a = 5) better predicted chest wall pain than did mEUD without weighting (a = 1) (C = 0.79 vs. 0.77 and U = 0.16 vs. 0.14). Body mass index (BMI) was significantly associated with chest wall pain (p = 0.008). On multivariable analysis, mEUD and BMI remained significant predictors of chest wall pain (p = 0.0003 and 0.03, respectively). CONCLUSION mEUD with moderate weighting better predicted chest wall pain than did V30, indicating that a small chest wall volume receiving a high radiation dose is responsible for chest wall pain. Independently of dose to the chest wall, BMI also correlated with chest wall pain.

Esophageal Dose Tolerance to Hypofractionated Stereotactic Body Radiation Therapy: Risk Factors for Late Toxicity

PURPOSE To identify factors associated with grade ≥3 treatment related late esophageal toxicity after lung or liver stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS This was a retrospective review of 52 patients with a planning target volume within 2 cm of the esophagus from a prospective registry of 607 lung and liver SBRT patients treated between 2005 and 2011. Patients were treated using a risk-adapted dose regimen to a median dose of 50 Gy in 5 fractions (range, 37.5-60 Gy in 3-10 fractions). Normal structures were contoured using Radiation Therapy Oncology Group (RTOG) defined criteria. RESULTS The median esophageal point dose and 1-cc dose were 32.3 Gy (range, 8.9-55.4 Gy) and 24.0 Gy (range, 7.8-50.9 Gy), respectively. Two patients had an esophageal fistula at a median of 8.4 months after SBRT, with maximum esophageal point doses of 51.5 and 52 Gy, and 1-cc doses of 48.1 and 50 Gy, respectively. These point and 1-cc doses were exceeded by 9 and 2 patients, respectively, without a fistula. The risk of a fistula for point doses exceeding 40, 45, and 50 Gy was 9.5% (n=2/21), 10.5% (n=2/19), and 12.5% (n=2/16), respectively. The risk of fistula for 1-cc doses exceeding 40, 45, and 50 Gy was 25% (n=2/9), 50% (n=2/4), and 50% (n=2/4), respectively. Eighteen patients received systemic therapy after SBRT (11 systemic chemotherapy, and 6 biologic agents, and 1 both). Both patients with fistulas had received adjuvant anti-angiogenic (vascular endothelial growth factor) agents within 2 months of completing SBRT. No patient had a fistula in the absence of adjuvant VEGF-modulating agents. CONCLUSIONS Esophageal fistula is a rare complication of SBRT. In this series, fistula was seen with esophageal point doses exceeding 51 Gy and 1-cc doses greater than 48 Gy. Notably, however, fistula was seen only in those patients who also received adjuvant VEGF-modulating agents after SBRT. The potential interaction of dose and adjuvant therapy should be considered when delivering SBRT near the esophagus.