N.E. Dunlap

Chest Wall Volume Receiving >30 Gy Predicts Risk of Severe Pain and/or Rib Fracture After Lung Stereotactic Body Radiotherapy

PURPOSE To identify the dose-volume parameters that predict the risk of chest wall (CW) pain and/or rib fracture after lung stereotactic body radiotherapy. METHODS AND MATERIALS From a combined, larger multi-institution experience, 60 consecutive patients treated with three to five fractions of stereotactic body radiotherapy for primary or metastatic peripheral lung lesions were reviewed. CW pain was assessed using the Common Toxicity Criteria for pain. Peripheral lung lesions were defined as those located within 2.5 cm of the CW. A minimal point dose of 20 Gy to the CW was required. The CW volume receiving >or=20, >or=30, >or=40, >or=50, and >or=60 Gy was determined and related to the risk of CW toxicity. RESULTS Of the 60 patients, 17 experienced Grade 3 CW pain and five rib fractures. The median interval to the onset of severe pain and/or fracture was 7.1 months. The risk of CW toxicity was fitted to the median effective concentration dose-response model. The CW volume receiving 30 Gy best predicted the risk of severe CW pain and/or rib fracture (R(2) = 0.9552). A volume threshold of 30 cm(3) was observed before severe pain and/or rib fracture was reported. A 30% risk of developing severe CW toxicity correlated with a CW volume of 35 cm(3) receiving 30 Gy. CONCLUSION The development of CW toxicity is clinically relevant, and the CW should be considered an organ at risk in treatment planning. The CW volume receiving 30 Gy in three to five fractions should be limited to <30 cm(3), if possible, to reduce the risk of toxicity without compromising tumor coverage.

Size matters: a comparison of T1 and T2 peripheral non-small-cell lung cancers treated with stereotactic body radiation therapy (SBRT).

OBJECTIVE The purpose of this study was to compare the outcomes and local control rates of patients with peripheral T1 and T2 non-small-cell lung cancer treated with stereotactic body radiation therapy. METHODS The records of 40 consecutive patients treated with 3- or 5-fraction lung stereotactic body radiation therapy for peripheral, clinical stage I non-small-cell lung cancer were reviewed. Stereotactic body radiation therapy was delivered at a median dose of 60 Gy. Doses to organs at risk were limited based on the Radiation Therapy Oncology Group 0236 treatment protocol. Patients were staged clinically. Median follow was 12.5 months. RESULTS Twenty-seven (67%) patients and 13 (33%) patients had T1 and T2 tumors, respectively. Thirty-seven (94%) patients were medically inoperable. Nine (23%) patients had chest wall pain after stereotactic body radiation therapy. Symptomatic pneumonitis developed in 4 (10%) patients. Increasing tumor size correlated with worse local control and overall survival. The median recurrence-free survival for T1 and T2 tumors was 30.6 months (95% confidence interval [CI], 26.9-34.2) and 20.5 months (95% CI, 14.3-26.5), respectively (P = .038). Local control at 2 years was 90% and 70% in T1 and T2 tumors, respectively (P = .03). The median survival for T1 and T2 tumors was 20 months (95% CI, 20.1-31.6) and 16.7 months (95% CI, 10.8-21.2), respectively (P = .073). CONCLUSIONS Stereotactic body radiation therapy for T2 non-small-cell lung cancer has a higher local recurrence rate and trended toward a worse survival than did T1 lesions. Tumor size is an important predictor of response to stereotactic body radiation therapy and should be considered in treatment planning.

Computed tomography-based anatomic assessment overestimates local tumor recurrence in patients with mass-like consolidation after stereotactic body radiotherapy for early-stage non-small cell lung cancer.

PURPOSE To investigate pulmonary radiologic changes after lung stereotactic body radiotherapy (SBRT), to distinguish between mass-like fibrosis and tumor recurrence. METHODS AND MATERIALS Eighty consecutive patients treated with 3- to 5-fraction SBRT for early-stage peripheral non-small cell lung cancer with a minimum follow-up of 12 months were reviewed. The mean biologic equivalent dose received was 150 Gy (range, 78-180 Gy). Patients were followed with serial CT imaging every 3 months. The CT appearance of consolidation was defined as diffuse or mass-like. Progressive disease on CT was defined according to Response Evaluation Criteria in Solid Tumors 1.1. Positron emission tomography (PET) CT was used as an adjunct test. Tumor recurrence was defined as a standardized uptake value equal to or greater than the pretreatment value. Biopsy was used to further assess consolidation in select patients. RESULTS Median follow-up was 24 months (range, 12.0-36.0 months). Abnormal mass-like consolidation was identified in 44 patients (55%), whereas diffuse consolidation was identified in 12 patients (15%), at a median time from end of treatment of 10.3 months and 11.5 months, respectively. Tumor recurrence was found in 35 of 44 patients with mass-like consolidation using CT alone. Combined with PET, 10 of the 44 patients had tumor recurrence. Tumor size (hazard ratio 1.12, P=.05) and time to consolidation (hazard ratio 0.622, P=.03) were predictors for tumor recurrence. Three consecutive increases in volume and increasing volume at 12 months after treatment in mass-like consolidation were highly specific for tumor recurrence (100% and 80%, respectively). Patients with diffuse consolidation were more likely to develop grade ≥ 2 pneumonitis (odds ratio 26.5, P=.02) than those with mass-like consolidation (odds ratio 0.42, P=.07). CONCLUSION Incorporating the kinetics of mass-like consolidation and PET to the current criteria for evaluating posttreatment response will increase the likelihood of correctly identifying patients with progressive disease after lung SBRT.

Pathophysiology of Radiation-Induced Dysphagia in Head and Neck Cancer

Oncologic treatments, such as curative radiotherapy and chemoradiation, for head and neck cancer can cause long-term swallowing impairments (dysphagia) that negatively impact quality of life. Radiation-induced dysphagia comprised a broad spectrum of structural, mechanical, and neurologic deficits. An understanding of the biomolecular effects of radiation on the time course of wound healing and underlying morphological tissue responses that precede radiation damage will improve options available for dysphagia treatment. The goal of this review is to discuss the pathophysiology of radiation-induced injury and elucidate areas that need further exploration.

HPV: A factor in organ preservation for locally advanced larynx and hypopharynx cancer?

PURPOSE/OBJECTIVE To assess the interaction of HPV/p16 status and therapy rendered in patients with locally advanced squamous cell carcinoma of the larynx and hypopharynx. MATERIALS AND METHODS Forty-seven consecutive patients receiving definitive treatment between 2009 and 2011 for locally advanced larynx or hypopharynx cancer with high-risk HPV and/or p16 testing performed were identified and retrospectively investigated. Overall survival (OS), disease-free survival (DFS), and local recurrence-free survival (LRFS) were assessed. RESULTS Of 47 evaluable patients, there were 38 (81%) with laryngeal and 9 (19%) with hypopharyngeal tumors, 13 (28%) of which were found to be either HPV or p16 positive. At a median follow-up of 24 months, comparing HPV/p16+ versus HPV/p16- patients, there was no difference in OS, DFS, or LRFS. There was an improvement in 2-year DFS (60% vs 100%, P=.03) and LRFS (80% vs 100%, P=.08), in HPV/p16+ patients treated with chemo/RT versus surgery. There was an improvement in 2-year DFS (100% vs 68%, P=.04) and LRFS (100% vs 72%, P=.05) in HPV/p16+ versus HPV/p16- patients who received chemo/RT. CONCLUSIONS Patients with HPV/p16+ tumors fared more favorably with chemo/RT than up-front surgery, with improvements in DFS and LRFS. In patients treated with the intent of organ preservation therapy, HPV/p16+ patients had no observed treatment failures. HPV/p16 status should be taken into account when considering organ preservation for locally advanced larynx and hypopharynx cancers.

Stereotactic Body Radiation Therapy as Salvage for Intrathoracic Recurrence in Patients With Previously Irradiated Locally Advanced Non-Small Cell Lung Cancer.

Introduction:The purpose of this study is to provide data on the outcomes of using stereotactic body radiotherapy (SBRT) as a means of salvage for non–small cell lung cancer (NSCLC) relapses previously treated with radiation. Materials and Methods:The records of 128 consecutive patients treated with thoracic SBRT from 2009 through 2012 were retrospectively reviewed. Twenty-seven patients (29 lesions) treated with prior thoracic radiation for stage IIB-IIIB NSCLC with subsequent recurrences and retreated with SBRT were identified. Results:The median prior radiation dose was 64.8 Gy (range, 45 to 74 Gy) with a median retreatment dose of 50 Gy (range, 30 to 54 Gy), corresponding to a biological equivalent dose of 100 Gy (range, 48 to 151 Gy), at a median time of 13.4 months from prior radiation. The mean follow-up after salvage SBRT was 22 months. Local failure following salvage was 11%, nodal failure was 37%, and distant failure was 30%. The local recurrence-free survival at 2 years was 72%. Out-of-field failure was predictive for worse local control (hazard ratio, 47.38; 95% confidence interval, 5.795-64.899). Progression-free survival at 1 year was 55% and 38% at 2 years. Overall survival at 2 years from SBRT salvage was 79%. Salvage biological equivalent dose ≥100 Gy was predictive of improved progression-free survival (48% vs. 18%, P=0.021) and overall survival (91% vs. 52%, P=0.004) at 2 years. The rate of symptomatic pneumonitis was 63% and chest wall pain reported was 26%. Conclusions:We observed improved outcomes following SBRT as a means of salvage for locally advanced recurrent NSCLC over traditional radiation therapy options. The toxicities were greater than expected from naive lung irradiation, but the adverse effects remained controlled with medications.

Tumor volume change with stereotactic body radiotherapy (SBRT) for early-stage lung cancer: evaluating the potential for adaptive SBRT.

Objectives:To quantify gross tumor volume (GTV) change during stereotactic body radiotherapy (SBRT) and on first follow-up, as well as to evaluate for any predictive prognostic risk factors related to GTV decrease. An attempt was also made to identify the potential timing for adaptive SBRT. Methods:Twenty-five tumors in 24 consecutive patients were treated with SBRT to total dose of 50 Gy in 5 fractions. Median age was 72.5 years. Tumor stage was T1, 68%; T2, 20%; and other, 12%. The GTVs of on the 5 cone-beam computed tomographies (CBCT1-5) obtained before each fraction and the first follow-up CT (CTPOST) were analyzed. Results:Median time from diagnosis to initiation of radiotherapy was 64 days. GTV on CBCT1 was the baseline for comparison. GTV decreased by a mean of 7% on CBCT2 (P=0.148), 11% on CBCT3 (P=0.364), 19% on CBCT4 (P=0.0021), and 32% on CBCT5 (P=0.0004). Univariate analyses of GTV shrinkage was significantly associated with “time from CBCT5 to CTPOST” (P=0.027) and “T-stage” (P=0.002). In multivariate analyses, “T-stage” remained significant with T1 tumors showing greater GTV shrinkage than T2 tumors. Conclusions:Significant decrease in GTV volume based on daily CBCT was demonstrated during SBRT treatment. Adaptive SBRT has the potential to minimize integral dose to the surrounding normal tissues without compromising GTV coverage.

Randomized Phase II Study Comparing Prophylactic Cranial Irradiation Alone to Prophylactic Cranial Irradiation and Consolidative Extracranial Irradiation for Extensive-Disease Small Cell Lung Cancer (ED SCLC): NRG Oncology RTOG 0937

Introduction: NRG Oncology RTOG 0937 is a randomized phase II trial evaluating 1‐year overall survival (OS) with prophylactic cranial irradiation (PCI) or PCI plus consolidative radiation therapy (PCI+cRT) to intrathoracic disease and extracranial metastases for extensive‐disease SCLC. Methods: Patients with one to four extracranial metastases were eligible after a complete response or partial response to chemotherapy. Randomization was to PCI or PCI+cRT to the thorax and metastases. Original stratification included partial response versus complete response after chemotherapy and one versus two to four metastases; age younger than 65 years versus 65 years or older was added after an observed imbalance. PCI consisted of 25 Gy in 10 fractions. cRT consisted of 45 Gy in 15 fractions. To detect an improvement in OS from 30% to 45% with a 34% hazard reduction (hazard ratio = 0.66) under a 0.1 type 1 error (one sided) and 80% power, 154 patients were required. Results: A total of 97 patients were randomized between March 2010 and February 2015. Eleven patients were ineligible (nine in the PCI group and two in the PCI+cRT group), leaving 42 randomized to receive PCI and 44 to receive PCI+cRT. At planned interim analysis, the study crossed the futility boundary for OS and was closed before meeting the accrual target. Median follow‐up was 9 months. The 1‐year OS was not different between the groups: 60.1% (95% confidence interval [CI]: 41.2–74.7) for PCI and 50.8% (95% CI: 34.0–65.3) for PCI+cRT (p = 0.21). The 3‐ and 12‐month rates of progression were 53.3% and 79.6% for PCI and 14.5% and 75% for PCI+cRT, respectively. Time to progression favored PCI+cRT (hazard ratio = 0.53, 95% CI: 0.32–0.87, p = 0.01). One patient in each arm had grade 4 therapy‐related toxicity and one had grade 5 therapy‐related pneumonitis with PCI+cRT. Conclusions: OS exceeded predictions for both arms. cRT delayed progression but did not improve 1‐year OS.

Stereotactic body radiation therapy for unbiopsied early-stage lung cancer: a multi-institutional analysis.

Objectives:Medically inoperable lung cancer patients often have comorbidities that preclude pathologic diagnosis from being attained. We perform a multi-institutional analysis to determine if unbiopsied early-stage lung carcinoma can be safely and effectively treated with stereotactic body radiation therapy (SBRT). Materials and Methods:Thirty-four patients with unbiopsied lung cancer were treated with SBRT at the University of Louisville or University of Virginia. Patients had computed tomography (CT) and positron emission tomography (PET) imaging clinically consistent with lung malignancy. Median SBRT dose was 50 Gy (range, 30 to 55 Gy) in a median of 5 fractions (range, 3 to 10 fractions) with static field SBRT or volumetric modulated arc therapy. Results:Median follow-up is 16.7 months. Primary tumors had a median longest dimension on the original CT of 1.6 cm (range, 0.5 to 3.3 cm) and posttreatment CT scan of 1.25 cm (range, 0.0 to 4.5 cm) (P=0.025). Median pretreatment standard uptake value on initial PET scan is 4.6 mg/mL (range, 0.0 to 16.2 mg/mL), and at a median of 7.6 months after SBRT, decreased to 2.25 mg/mL (range, 0.0 to 10.9 mg/mL) on posttreatment PET (P=0.002). Crude local control is 97.1%. The estimated 2-year regional control is 80%, distant control 85%, and overall survival 85%. There were no grade 3 or greater acute toxicities and only 3 grade 3 chronic treatment-related toxicitities. Discussion:In medically inoperable patients with unbiopsied lung cancer, local control can be achieved with minimal toxicity with the use of SBRT. The use of SBRT for unbiopsied early-stage lung cancer patients should be performed in a multidisciplinary setting and after detailed discussion with the patient about the risks and benefits of SBRT.

Accurate Lungs Segmentation on CT Chest Images by Adaptive Appearance-Guided Shape Modeling

To accurately segment pathological and healthy lungs for reliable computer-aided disease diagnostics, a stack of chest CT scans is modeled as a sample of a spatially inhomogeneous joint 3D Markov-Gibbs random field (MGRF) of voxel-wise lung and chest CT image signals (intensities). The proposed learnable MGRF integrates two visual appearance sub-models with an adaptive lung shape submodel. The first-order appearance submodel accounts for both the original CT image and its Gaussian scale space (GSS) filtered version to specify local and global signal properties, respectively. Each empirical marginal probability distribution of signals is closely approximated with a linear combination of discrete Gaussians (LCDG), containing two positive dominant and multiple sign-alternate subordinate DGs. The approximation is separated into two LCDGs to describe individually the lungs and their background, i.e., all other chest tissues. The second-order appearance submodel quantifies conditional pairwise intensity dependencies in the nearest voxel 26-neighborhood in both the original and GSS-filtered images. The shape submodel is built for a set of training data and is adapted during segmentation using both the lung and chest appearances. The accuracy of the proposed segmentation framework is quantitatively assessed using two public databases (ISBI VESSEL12 challenge and MICCAI LOLA11 challenge) and our own database with, respectively, 20, 55, and 30 CT images of various lung pathologies acquired with different scanners and protocols. Quantitative assessment of our framework in terms of Dice similarity coefficients, 95-percentile bidirectional Hausdorff distances, and percentage volume differences confirms the high accuracy of our model on both our database (98.4±1.0%, 2.2±1.0 mm, 0.42±0.10%) and the VESSEL12 database (99.0±0.5%, 2.1±1.6 mm, 0.39±0.20%), respectively. Similarly, the accuracy of our approach is further verified via a blind evaluation by the organizers of the LOLA11 competition, where an average overlap of 98.0% with the experts segmentation is yielded on all 55 subjects with our framework being ranked first among all the state-of-the-art techniques compared.To accurately segment pathological and healthy lungs for reliable computer-aided disease diagnostics, a stack of chest CT scans is modeled as a sample of a spatially inhomogeneous joint 3D Markov-Gibbs random field (MGRF) of voxel-wise lung and chest CT image signals (intensities). The proposed learnable MGRF integrates two visual appearance sub-models with an adaptive lung shape submodel. The first-order appearance submodel accounts for both the original CT image and its Gaussian scale space (GSS) filtered version to specify local and global signal properties, respectively. Each empirical marginal probability distribution of signals is closely approximated with a linear combination of discrete Gaussians (LCDG), containing two positive dominant and multiple sign-alternate subordinate DGs. The approximation is separated into two LCDGs to describe individually the lungs and their background, i.e., all other chest tissues. The second-order appearance submodel quantifies conditional pairwise intensity dependencies in the nearest voxel 26-neighborhood in both the original and GSS-filtered images. The shape submodel is built for a set of training data and is adapted during segmentation using both the lung and chest appearances. The accuracy of the proposed segmentation framework is quantitatively assessed using two public databases (ISBI VESSEL12 challenge and MICCAI LOLA11 challenge) and our own database with, respectively, 20, 55, and 30 CT images of various lung pathologies acquired with different scanners and protocols. Quantitative assessment of our framework in terms of Dice similarity coefficients, 95-percentile bidirectional Hausdorff distances, and percentage volume differences confirms the high accuracy of our model on both our database (98.4±1.0%, 2.2±1.0 mm, 0.42±0.10%) and the VESSEL12 database (99.0±0.5%, 2.1±1.6 mm, 0.39±0.20%), respectively. Similarly, the accuracy of our approach is further verified via a blind evaluation by the organizers of the LOLA11 competition, where an average overlap of 98.0% with the experts segmentation is yielded on all 55 subjects with our framework being ranked first among all the state-of-the-art techniques compared.