[show abstract][hide abstract] ABSTRACT: There are scant data regarding the effects of prophylactic cranial irradiation (PCI) on neurocognitive function (NCF) and quality of life (QOL). Radiation Therapy Oncology Group trial 0214 showed no overall survival (OS) benefit for PCI in stage III non-small-cell lung cancer (NSCLC) at 1 year. However, there was a significant decrease in brain metastases (BM). This analysis focuses on the impact of PCI on NCF and QOL.
Patients with stage III NSCLC who completed definitive therapy without progression were randomly assigned to PCI or observation. NCF was assessed with Mini-Mental Status Examination (MMSE), Activities of Daily Living Scale (ADLS), and Hopkins Verbal Learning Test (HVLT). QOL was assessed with the European Organisation for Research and Treatment of Cancer (EORTC) core tool (QOL Questionnaire-QLQC30) and brain module (QLQBN20).
There were no statistically significant differences at 1 year between the two arms in any component of the EORTC-QLQC30 or QLQBN20 (P > .05), although a trend for greater decline in patient-reported cognitive functioning with PCI was noted. There were no significant differences in MMSE (P = .60) or ADLS (P = .88). However, for HVLT, there was greater decline in immediate recall (P = .03) and delayed recall (P = .008) in the PCI arm at 1 year.
PCI in stage III NSCLC significantly decreases the risk of BM without improving 1-year OS. There were no significant differences in global cognitive function (MMSE) or QOL after PCI, but there was a significant decline in memory (HVLT) at 1 year. This study provides prospective data regarding the relative risks and benefits of PCI in this setting and the need to use sensitive cognitive assessments.
Journal of Clinical Oncology 01/2011; 29(3):279-86. · 18.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: Owing to a low efficiency of gene transfer when delivered systemically, gene therapy may find its greatest utility in the
clinic when combined with loco-regional cancer treatment such as radiation therapy. Although a variety of gene therapy strategies
have been combined with radiation in preclinical models, only a handful have been translated into the clinic. Overall, combining
gene therapy with radiation therapy has been well tolerated. Most of the gene therapy-related adverse events have been mild
to moderate, transient, produced no noticeable symptoms to the patient, and did not exacerbate the side effects of radiation
therapy. Several strategies have demonstrated antitumor activity in early-stage trials, and at least two have progressed to
phase 3. Future developments will be driven by a better understanding of the radiation response and molecular basis for tumor
KeywordsGene therapy-Radiation therapy-Radiosensitizer-Adenovirus-Suicide gene therapy-Oncolysis-p53-TNFα, EGFR-Ku70
[show abstract][hide abstract] ABSTRACT: Lung cancer is a leading cause of cancer deaths for both men and women across the world. In the past, studies on lung cancer have focused on traditional end points such as survival, disease-free survival or local control. More recently, investigators have begun to appreciate the importance of health-related quality-of-life outcomes, particularly in the setting of lung cancer. This article provides an overview of the importance, methodology, analysis and presentation of health-related quality of life in lung cancer trials, and also discusses some of the limitations and challenges of such studies.
Expert Review of Pharmacoeconomics & Outcomes Research 12/2010; 10(6):667-76. · 1.67 Impact Factor
[show abstract][hide abstract] ABSTRACT: "The American College of Radiology seeks and encourages collaboration with other organizations on the development of the ACR Appropriateness Criteria through society representation on expert panels. Participation by representatives from collaborating societies on the expert panel does not necessarily imply society endorsement of the final document."
International journal of radiation oncology, biology, physics 11/2010; 78(4):969-74. · 4.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: In order to appropriately manage patients with lung cancer, it is necessary to properly stage the tumor. The ACR Appropriateness Criteria is designed to provide an overview of the value of different imaging techniques in the non-invasive staging of lung cancer and allow for the rational selection of imaging studies to arrive at the appropriate clinical stage.
Journal of thoracic imaging 11/2010; 25(4):W107-11. · 1.42 Impact Factor
[show abstract][hide abstract] ABSTRACT: Recently, many agents have been identified that target molecular pathways that can mitigate radiation toxicity. To date, no drugs have been approved as radiation injury mitigators, which are defined as agents administered after irradiation but before toxicity is manifest. In order to accelerate the application of potential mitigators for cancer patients, a meeting sponsored by the National Cancer Institute (NCI) and National Institute of Allergy and Infectious Diseases (NIAID) was held in January 2010. This article presents an algorithm to guide clinical trials for such agents in patients receiving radiotherapy or radiochemotherapy. It reviews the mechanisms of radiation injury, the clinical problem, the preclinical and clinical development of candidate agents, and the design and conduct of clinical trials. The central role of patient reported outcomes is outlined, as well as key lessons learned from prior clinical trials. Ultimately, the goal is to be able to apply such promising agents to improve the quality of life for patients receiving radiotherapy or chemoradiotherapy for cancer.
Clinical Cancer Research 11/2010; 17(2):222-8. · 7.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: The authors propose a combined scatter reduction and correction method to improve image quality in cone-beam computed tomography (CBCT). Although using a beam-block approach similar to previous techniques to measure the scatter, this method differs in that the authors utilize partially blocked projection data obtained during scatter measurement for CBCT image reconstruction. This study aims to evaluate the feasibility of the proposed approach.
A 1D grid, composed of lead septa, was placed between the radiation source and the imaging object for scatter measurement. Image data were collected from the grid interspace regions while the scatter distribution was measured in the blocked regions under the grid. Scatter correction was performed by subtracting the measured scatter from the imaging data. Image information in the penumbral regions of the grid was derived. Three imaging modes were developed to reconstruct full CBCT images from partial projection data. The single-rotation half-fan mode uses interpolation to fill the missing data. The dual-rotation half-fan mode uses two rotations, with the grid offset by half a grid cycle, to acquire two complementary sets of projections, which are then merged to form complete projections for reconstruction. The single-rotation full-fan mode was designed for imaging a small object or a region of interest. Full-fan projection images were acquired over a 360 degrees scan angle with the grid shifting a distance during the scan. An enlarged Catphan phantom was used to evaluate potential improvement in image quality with the proposed technique. An anthropomorphic pelvis phantom was used to validate the feasibility of reconstructing a complete set of CBCT images from the partially blocked projections using three imaging modes. Rigid-body image registration was performed between the CBCT images from the single-rotation half-fan mode and the simulation CT and the results were compared to that for the CBCT images from dual-rotation mode and conventional CBCT images.
The proposed technique reduced the streak artifact index from 58% to 1% in comparison with the conventional CBCT. It also improved CT number linearity from 0.880 to 0.998 and the contrast-to-noise ratio (CNR) from 4.29 to 6.42. Complete sets of CBCT images with overall improved image quality were achieved for all three image modes. The longitudinal resolution was slightly compromised for the single-rotation half-fan mode. High resolution was retained for the dual-rotation half-fan and single-rotation full-fan modes in the longitudinal direction. The registration error for the CBCT images from the single-rotation half-fan mode was 0.8 +/- 0.3 mm in the longitudinal direction and negligible in the other directions.
The proposed method provides combined scatter correction and direct scatter reduction. Scatter correction may eliminate scatter artifacts, while direct scatter reduction may improve the CNR to compensate the CNR degradation due to scatter correction. Complete sets of CBCT images are reconstructed in all three imaging modes. The single-rotation mode can be used for rigid-body patient alignment despite degradation in longitudinal resolution. The dual-rotation mode may be used to improve CBCT image quality for soft tissue delineation in adaptive radiation therapy.
Medical Physics 11/2010; 37(11):5634-44. · 2.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: Patients treated with chemoradiotherapy for locally advanced non-small-cell lung carcinoma (LA-NSCLC) were analyzed for local-regional failure (LRF) and overall survival (OS) with respect to radiotherapy dose intensity.
This study combined data from seven Radiation Therapy Oncology Group (RTOG) trials in which chemoradiotherapy was used for LA-NSCLC: RTOG 88-08 (chemoradiation arm only), 90-15, 91-06, 92-04, 93-09 (nonoperative arm only), 94-10, and 98-01. The radiotherapeutic biologically effective dose (BED) received by each individual patient was calculated, as was the overall treatment time-adjusted BED (tBED) using standard formulae. Heterogeneity testing was done with chi-squared statistics, and weighted pooled hazard ratio estimates were used. Cox and Fine and Gray's proportional hazard models were used for OS and LRF, respectively, to test the associations between BED and tBED adjusted for other covariates.
A total of 1,356 patients were analyzed for BED (1,348 for tBED). The 2-year and 5-year OS rates were 38% and 15%, respectively. The 2-year and 5-year LRF rates were 46% and 52%, respectively. The BED (and tBED) were highly significantly associated with both OS and LRF, with or without adjustment for other covariates on multivariate analysis (p < 0.0001). A 1-Gy BED increase in radiotherapy dose intensity was statistically significantly associated with approximately 4% relative improvement in survival; this is another way of expressing the finding that the pool-adjusted hazard ratio for survival as a function of BED was 0.96. Similarly, a 1-Gy tBED increase in radiotherapy dose intensity was statistically significantly associated with approximately 3% relative improvement in local-regional control; this is another way of expressing the finding that the pool-adjusted hazard ratio as a function of tBED was 0.97.
Higher radiotherapy dose intensity is associated with improved local-regional control and survival in the setting of chemoradiotherapy.
International journal of radiation oncology, biology, physics 10/2010; 82(1):425-34. · 4.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: For some cancers, married individuals present with less advanced stage of disease, receive more aggressive treatment, and live longer after diagnosis compared with unmarried individuals. We examined survival differences by marital status among women with cervical cancer using a population-based sample of patients in the United States while considering patient, tumor, and treatment characteristics.
We identified 7,997 women (1,835 single, 3,849 married, 1,193 separated/divorced, and 1,120 widowed) diagnosed with primary invasive cervical cancer from 1992 to 1996 (with follow-up through December 31, 2004) from the Surveillance, Epidemiology, and End Results program. Associations of marital status, race, age at diagnosis, tumor grade, tumor stage, cancer-directed radiotherapy, and cancer-directed surgery with survival were examined using Cox proportional hazard regression models.
Five-year survival was highest for married women and lowest for widowed women (p <.0001). Compared with married women, risks of death for single, separated/divorced, and widowed women were 1.13 (95% confidence interval [CI] = 1.03-1.25), 1.41 (95% CI = 1.28-1.57), and 2.51 (95% CI = 2.29-2.76), respectively. After adjustment, marital status was not independently associated with risk of death (p =.21), although it interacted with tumor stage and cancer-directed radiation therapy. Married women with early stage disease who did not receive radiation therapy had improved survival compared with single, separated/divorced, or widowed women.
Marital status interacted with tumor stage and cancer-directed radiation therapy to influence survival among women with cervical cancer. Additional study of the pathways through which partner status influences survival after cancer diagnosis could inform the development of social support interventions.
[show abstract][hide abstract] ABSTRACT: To review the dose limits and standardize the three-dimenional (3D) radiographic definition for the organs at risk (OARs) for thoracic radiotherapy (RT), including the lung, proximal bronchial tree, esophagus, spinal cord, ribs, and brachial plexus.
The present study was performed by representatives from the Radiation Therapy Oncology Group, European Organization for Research and Treatment of Cancer, and Soutwestern Oncology Group lung cancer committees. The dosimetric constraints of major multicenter trials of 3D-conformal RT and stereotactic body RT were reviewed and the challenges of 3D delineation of these OARs described. Using knowledge of the human anatomy and 3D radiographic correlation, draft atlases were generated by a radiation oncologist, medical physicist, dosimetrist, and radiologist from the United States and reviewed by a radiation oncologist and medical physicist from Europe. The atlases were then critically reviewed, discussed, and edited by another 10 radiation oncologists.
Three-dimensional descriptions of the lung, proximal bronchial tree, esophagus, spinal cord, ribs, and brachial plexus are presented. Two computed tomography atlases were developed: one for the middle and lower thoracic OARs (except for the heart) and one focusing on the brachial plexus for a patient positioned supine with their arms up for thoracic RT. The dosimetric limits of the key OARs are discussed.
We believe these atlases will allow us to define OARs with less variation and generate dosimetric data in a more consistent manner. This could help us study the effect of radiation on these OARs and guide high-quality clinical trials and individualized practice in 3D-conformal RT and stereotactic body RT.
International journal of radiation oncology, biology, physics 10/2010; 81(5):1442-57. · 4.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: Modern cancer treatment techniques, such as intensity-modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT), have greatly increased the demand for more accurate treatment planning (structure definition, dose calculation, etc) and dose delivery. The ability to use fast and accurate Monte Carlo (MC)-based dose calculations within a commercial treatment planning system (TPS) in the clinical setting is now becoming more of a reality. This study describes the dosimetric verification and initial clinical evaluation of a new commercial MC-based photon beam dose calculation algorithm, within the iPlan v.4.1 TPS (BrainLAB AG, Feldkirchen, Germany). Experimental verification of the MC photon beam model was performed with film and ionization chambers in water phantoms and in heterogeneous solid-water slabs containing bone and lung-equivalent materials for a 6 MV photon beam from a Novalis (BrainLAB) linear accelerator (linac) with a micro-multileaf collimator (m(3) MLC). The agreement between calculated and measured dose distributions in the water phantom verification tests was, on average, within 2%/1 mm (high dose/high gradient) and was within +/-4%/2 mm in the heterogeneous slab geometries. Example treatment plans in the lung show significant differences between the MC and one-dimensional pencil beam (PB) algorithms within iPlan, especially for small lesions in the lung, where electronic disequilibrium effects are emphasized. Other user-specific features in the iPlan system, such as options to select dose to water or dose to medium, and the mean variance level, have been investigated. Timing results for typical lung treatment plans show the total computation time (including that for processing and I/O) to be less than 10 min for 1-2% mean variance (running on a single PC with 8 Intel Xeon X5355 CPUs, 2.66 GHz). Overall, the iPlan MC algorithm is demonstrated to be an accurate and efficient dose algorithm, incorporating robust tools for MC-based SBRT treatment planning in the routine clinical setting.
Physics in Medicine and Biology 08/2010; 55(16):4445-64. · 2.70 Impact Factor
[show abstract][hide abstract] ABSTRACT: The goal of radiation therapy is to reduce or eliminate tumor burden while sparing normal tissues from long-term injury. Thoracic radiation presents a unique challenge because of the inherent sensitivity of normal lung tissue to radiation. Damage to normal lung tissue presents a major obstacle in the treatment of individuals. To overcome this problem, a number of strategies are being used, including the modulation of dose volume, the use of image-guided radiotherapy, and the use of agents designed to reduce lung injury from radiation. Herein we discuss our current knowledge of the molecular and cellular events that occur after radiation therapy, the clinical manifestations of radiation-induced lung injury, current strategies to minimize lung injury, and recent experimental methods to reduce lung injury and their potential for translation into the clinic.
Seminars in radiation oncology 07/2010; 20(3):201-7. · 4.32 Impact Factor
[show abstract][hide abstract] ABSTRACT: A meta-analysis was conducted to determine the influence of gender, race, and marital status on overall survival (OS) in Radiation Therapy Oncology Group nonoperative non-small cell lung cancer trials.
Data from 1365 patients treated on nine prospective Radiation Therapy Oncology Group studies activated during the 1990s were analyzed. Impact of gender, marital status, and race was considered in the Cox proportional hazards models. Age, Karnofsky performance status, weight loss, stage, histology, location of primary tumor, biologic equivalent dose, deviation from protocol dose, and education level were adjusted in the model. A two-sided p value <0.05 was considered statistically significant.
Males had significantly higher mortality than females adjusted for other covariates (hazard ratio [HR] 1.22, 95% confidence interval 1.08 -1.38). Race and marital status were not independently predictive for OS. Single females had significantly better OS than single males (HR 0.72), and married males had lower OS than single females (HR 1.36).
These results suggest that although certain subgroups of gender, race, and/or marital status have better outcomes with respect to OS; gender seems to be the most significant factor influencing survival results among nonoperative non-small cell lung cancer patients.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 05/2010; 5(5):631-9. · 4.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: To evaluate different similarity metrics (SM) using natural calcifications and observation-based measures to determine the most accurate prostate and seminal vesicle localization on daily cone-beam CT (CBCT) images.
CBCT images of 29 patients were retrospectively analyzed; 14 patients with prostate calcifications (calcification data set) and 15 patients without calcifications (no-calcification data set). Three groups of test registrations were performed. Test 1: 70 CT/CBCT pairs from calcification dataset were registered using 17 SMs (6,580 registrations) and compared using the calcification mismatch error as an endpoint. Test 2: Using the four best SMs from Test 1, 75 CT/CBCT pairs in the no-calcification data set were registered (300 registrations). Accuracy of contour overlays was ranked visually. Test 3: For the best SM from Tests 1 and 2, accuracy was estimated using 356 CT/CBCT registrations. Additionally, target expansion margins were investigated for generating registration regions of interest.
Test 1-Incremental sign correlation (ISC), gradient correlation (GC), gradient difference (GD), and normalized cross correlation (NCC) showed the smallest errors (mu +/- sigma: 1.6 +/- 0.9 approximately 2.9 +/- 2.1 mm). Test 2-Two of the three reviewers ranked GC higher. Test 3-Using GC, 96% of registrations showed <3-mm error when calcifications were filtered. Errors were left/right: 0.1 +/- 0.5mm, anterior/posterior: 0.8 +/- 1.0mm, and superior/inferior: 0.5 +/- 1.1 mm. The existence of calcifications increased the success rate to 97%. Expansion margins of 4-10 mm were equally successful.
Gradient-based SMs were most accurate. Estimated error was found to be <3 mm (1.1 mm SD) in 96% of the registrations. Results suggest that the contour expansion margin should be no less than 4 mm.
International journal of radiation oncology, biology, physics 04/2010; 77(4):1257-65. · 4.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: Stereotactic Radiotherapy (SRT) is more commonly used for skull base tumors in conjunction with the technical development of radiation intensity modulation. Purpose of this study is to correlate clinical and radiographic characteristics of delayed radiation injury (RI) occurring around central skull base following SRT with SRT dosimetric data. Total of six patients were identified to have developed RI in the vicinity of SRT target volume out of 141 patients who received SRT in he center or near-center of the skull base. The images and medical records were retrospectively reviewed. The analysis was performed for RI location, time of development, imaging and clinical characteristics and evolution of RI and correlated with SRT dosimetric analysis using image fusion with follow-up MRI scans. Mean follow-up time was 24 +/- 9 months. During the follow-up period, twelve sites of RI were found in 6 patients. They were clinically symptomatic in 4/6 patients (66.6%) at median 12.5 months after SRT. Mean time interval between SRT and detection of RI was 9 +/- 3, 18.5 +/- 5, and 13.5 months for brainstem, temporal lobe, and cerebellum/labyrinth lesions, respectively. All RI lesions were included in the region of high SRT doses. After steroid and symptomatic treatment, 50% of RI lesions showed complete response, and 40% showed partial response. RI can occur around the skull base because of irregular shape of target tumor, its close proximity to normal brain parenchyma, and inhomogeneity of dose distribution. Brainstem lesions occurred earlier than temporal lobe RI. The majority of the RI lesions, not mixed with the tumor in this study, showed radiographic and clinical improvement with steroid and symptomatic treatments.
Journal of Neuro-Oncology 04/2010; 98(2):177-84. · 3.12 Impact Factor
[show abstract][hide abstract] ABSTRACT: Southwest Oncology Group 9504 demonstrated the feasibility and potential benefit of docetaxel consolidation after etoposide, cisplatin, and radiotherapy in patients with locally advanced non-small cell lung cancer. Our study assessed consolidation with either gemcitabine alone or with docetaxel after identical chemoradiation as used in Southwest Oncology Group 9504.
Patients with stage III non-small cell lung cancer and good performance status were included. Treatment consisted of concurrent cisplatin 50 mg/m on days 1 and 8 plus etoposide 50 mg/m on days 1 to 5 for two 28-day cycles plus radiotherapy (62 Gy, 2 Gy daily in 31 fractions over 7 weeks), followed by randomization to either gemcitabine 1000 mg/m on days 1 and 8 (G) or gemcitabine 1000 mg/m on days 1 and 8 plus docetaxel 75 mg/m on day 1 (GD) every 21 days for three cycles.
Eighty-three patients were entered, 81 received induction therapy, and 64 were randomized (32 in each arm). Grade 3 or four events, including neutropenia (56.3% vs. 28.1%, p = 0.03), anemia (18.8% vs. 3.1%, p = 0.05), and fatigue (15.6% vs. 6.3%, p = NS), were more frequent with GD compared with G. Among all patients, median survival from registration was 20.8 months (95% confidence interval: 16.4-33.8), and 2-year survival was 46.7% (95% confidence interval: 35.6-57.1). From randomization, median progression-free survival was 5.4 months for G and 13.4 months for GD, and median survival was 16.1 months for G and 29.5 months for GD. Two-year survival rates were 40.6% for G and 55.7% for GD.
The doublet, as expected, resulted in more toxicity, particularly myelosuppression and fatigue. Survival associated with the GD treatment arm of this trial exceeds that of previously reported trials.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 03/2010; 5(5):673-9. · 4.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: Surgical decompression of metastatic epidural compression (MEC) improved ambulatory function. Spine radiosurgery can accurately target the epidural tumor and deliver high radiation doses for tumor control. Therefore, a clinical trial was performed to quantitatively determine the degree of epidural decompression by radiosurgery of metastatic epidural compression.
Sixty-two patients with a total of 85 lesions of metastatic epidural compression were treated. Epidural compression was diagnosed by magnetic resonance imaging (MRI) scans. Main criteria of inclusion were neurological status with muscle power 4 of 5 or better. Radiosurgery was performed to the involved spine segment, including the epidural mass with median dose of 16 Gy (range 12-20 Gy) in a single session. All patients had prospective clinical follow-up, ranging from 1-48 months (median 11.5 months), and 36 patients had pretreatment and post-treatment imaging, ranging from 2-33 months (median 9.3 months). Primary endpoints were epidural tumor control and thecal sac decompression.
The mean epidural tumor volume reduction was 65 +/- 14% at 2 months after radiosurgery. The epidural tumor area at the level of the most severe spinal cord compression was 0.82 +/- 0.08 cm(2) before radiosurgery and 0.41 +/- 0.06 cm(2) after radiosurgery (P < .001). Thecal sac patency improved from 55 +/- 4% to 76 +/- 3% (P < .001). Overall, neurological function improved in 81%.
This study demonstrated a radiosurgical decompression of epidural tumor. Although neurosurgical decompression and radiotherapy is the standard treatment in patients with good performance, radiosurgical decompression can be a viable noninvasive treatment option for malignant epidural compression.
Cancer 03/2010; 116(9):2250-7. · 5.20 Impact Factor