Glioblastoma radiomics: can genomic and molecular characteristics correlate with imaging response patterns?

PURPOSE: For glioblastoma (GBM), imaging response (IR) or pseudoprogression (PSP) is frequently observed after chemoradiation and may connote a favorable prognosis. With tumors categorized by the Cancer Genome Atlas Project (mesenchymal, classical, neural, and proneural) and by methylguanine-methyltransferase (MGMT) methylation status, we attempted to determine if certain genomic or molecular subtypes of GBM were specifically associated with IR or PSP. METHODS: Patients with GBM treated at two institutions were reviewed. Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Mantel-cox test determined effect of IR and PSP on OS and PFS. Fisher's exact test was utilized to correlate IR and PSP with genomic subtypes and MGMT status. RESULTS: Eighty-two patients with GBM were reviewed. The median OS and PFS were 17.9 months and 8.9 months. IR was observed in 28 (40%) and was associated with improved OS (median 29.4 vs 14.5 months p < 0.01) and PFS (median 17.7 vs 5.5 months, p < 0.01). PSP was observed in 14 (19.2%) and trended towards improved PFS (15.0 vs 7.7 months p = 0.08). Tumors with a proneural component had a higher rate of IR compared to those without a proneural component (IR 60% vs 28%; p = 0.03). MGMT methylation was associated with IR (58% vs 24%, p = 0.032), but not PSP (34%, p = 0.10). CONCLUSION: IR is associated with improved OS and PFS. The proneural subtype and MGMT methylated tumors had higher rates of IR.

Hippocampal dose volume histogram predicts Hopkins Verbal Learning Test scores after brain irradiation.

PURPOSE: Radiation-induced cognitive decline is relatively common after treatment for primary and metastatic brain tumors; however, identifying dosimetric parameters that are predictive of radiation-induced cognitive decline is difficult due to the heterogeneity of patient characteristics. The memory function is especially susceptible to radiation effects after treatment. The objective of this study is to correlate volumetric radiation doses received by critical neuroanatomic structures to post-radiation therapy (RT) memory impairment. METHODS AND MATERIALS: Between 2008 and 2011, 53 patients with primary brain malignancies were treated with conventionally fractionated RT in prospectively accrued clinical trials performed at our institution. Dose-volume histogram analysis was performed for the hippocampus, parahippocampus, amygdala, and fusiform gyrus. Hopkins Verbal Learning Test-Revised scores were obtained at least 6 months after RT. Impairment was defined as an immediate recall score ≤15. For each anatomic region, serial regression was performed to correlate volume receiving a given dose (VD(Gy)) with memory impairment. RESULTS: Hippocampal V53.4Gy to V60.9Gy significantly predicted post-RT memory impairment (P < .05). Within this range, the hippocampal V55Gy was the most significant predictor (P = .004). Hippocampal V55Gy of 0%, 25%, and 50% was associated with tumor-induced impairment rates of 14.9% (95% confidence interval [CI], 7.2%-28.7%), 45.9% (95% CI, 24.7%-68.6%), and 80.6% (95% CI, 39.2%-96.4%), respectively. CONCLUSIONS: The hippocampal V55Gy is a significant predictor for impairment, and a limiting dose below 55 Gy may minimize radiation-induced cognitive impairment.

Emerging Indications for Fractionated Gamma Knife Radiosurgery.

BACKGROUND: Gamma Knife radiosurgery (GKRS) allows for the treatment of intracranial tumors with a high degree of dose conformality and precision. There are, however, certain situations wherein the dose conformality of GKRS is desired, but single session treatment is contraindicated. In these situations, a traditional pin-based GKRS head frame cannot be used, as it precludes fractionated treatment. OBJECTIVE: To report our experience in treating patients with fractionated GKRS using a relocatable, noninvasive immobilization system. METHODS: Patients were considered candidates for fractionated GKRS if they had one or more of the following indications: a benign tumor >10 cc in volume or abutting the optic pathway, a vestibular schwannoma with the intent of hearing preservation, or a tumor previously irradiated with single fraction GKRS. The immobilization device used for all patients was the Extend system (Leksell Gamma Knife Perfexion, Elekta, Kungstensgatan, Stockholm). RESULTS: We identified 34 patients treated with fractionated GKRS between August 2013 and February 2015. There were a total of 37 tumors treated including 15 meningiomas, 11 pituitary adenomas, 6 brain metastases, 4 vestibular schwannomas, and 1 hemangioma. At last follow-up, all 21 patients treated for perioptic tumors had stable or improved vision and all 4 patients treated for vestibular schwannoma maintained serviceable hearing. No severe adverse events were reported. CONCLUSION: Fractionated GKRS was well-tolerated in the treatment of large meningiomas, perioptic tumors, vestibular schwannomas with intent of hearing preservation, and in reirradiation of previously treated tumors.

Predictors of neurologic and nonneurologic death in patients with brain metastasis initially treated with upfront stereotactic radiosurgery without whole-brain radiation therapy.

Background: In this study we attempted to discern the factors predictive of neurologic death in patients with brain metastasis treated with upfront stereotactic radiosurgery (SRS) without whole brain radiation therapy (WBRT) while accounting for the competing risk of nonneurologic death. Methods: We performed a retrospective single-institution analysis of patients with brain metastasis treated with upfront SRS without WBRT. Competing risks analysis was performed to estimate the subdistribution hazard ratios (HRs) for neurologic and nonneurologic death for predictor variables of interest. Results: Of 738 patients treated with upfront SRS alone, neurologic death occurred in 226 (30.6%), while nonneurologic death occurred in 309 (41.9%). Multivariate competing risks analysis identified an increased hazard of neurologic death associated with diagnosis-specific graded prognostic assessment (DS-GPA) ≤ 2 (P = .005), melanoma histology (P = .009), and increased number of brain metastases (P<.001), while there was a decreased hazard associated with higher SRS dose (P = .004). Targeted agents were associated with a decreased HR of neurologic death in the first 1.5 years (P = .04) but not afterwards. An increased hazard of nonneurologic death was seen with increasing age (P =.03), nonmelanoma histology (P<.001), presence of extracranial disease (P<.001), and progressive systemic disease (P =.004). Conclusions: Melanoma, DS-GPA, number of brain metastases, and SRS dose are predictive of neurologic death, while age, nonmelanoma histology, and more advanced systemic disease are predictive of nonneurologic death. Targeted agents appear to delay neurologic death.

Impact of timing of radiotherapy in patients with newly diagnosed glioblastoma.

OBJECTIVE: To further evaluate if a delay in the start of radiation therapy (RT) affects patient outcomes for glioblastoma (GBM). PATIENTS AND METHODS: From May 1999 to May 2010, a total of 161 patients underwent surgery followed by RT for GBM. We assessed overall survival (OS) and progression free survival (PFS), stratified by extent of surgical resection. Included in the analysis were genomic predictors of progression. RESULTS: Median time from surgery to start of RT was 20days for biopsy alone, 28days for subtotal resection (STR) and 28days for gross total resection (GTR). For all patients, a delay >28days did not result in a difference in PFS when compared to no delay (6.7 vs. 6.9 months, p=0.07). PFS was improved in biopsy or STR patients with a >28day delay to start of RT (4.2 vs. 6.7 months, p=0.006). OS was also improved in patients receiving biopsy or STR with a >28day delay to start of RT (12.3 vs. 7.8 months, p=0.005). Multivariable analysis (MVA) demonstrated an improvement in OS and PFS with time to RT >28days for biopsy or STR patients (HR 0.52 p=0.008 and HR 0.48 p=0.02, respectively). CONCLUSION: In this retrospective review of GBM patients treated at a single institution, OS and PFS were not different between time to RT >28days compared to <28 days. There was a modest improvement in both PFS and OS in patients who received biopsy or STR with time to RT >28 days.

Is a Clinical Target Volume (CTV) Necessary in the Treatment of Lung Cancer in the Modern Era Combining 4-D Imaging and Image-guided Radiotherapy (IGRT)?

OBJECTIVE: We hypothesized that omission of clinical target volumes (CTV) in lung cancer radiotherapy would not compromise control by determining retrospectively if the addition of a CTV would encompass the site of failure. METHODS: Stage II-III patients were treated from 2009-2012 with daily cone-beam imaging and a 5 mm planning target volume (PTV) without a CTV. PTVs were expanded 1 cm and termed CTVretro. Recurrences were scored as 1) within the PTV, 2) within CTVretro, or 3) outside the PTV. Locoregional control (LRC), distant control (DC), progression-free survival (PFS), and overall survival (OS) were estimated. RESULT: Among 110 patients, Stage IIIA 57%, IIIB 32%, IIA 4%, and IIB 7%. Eighty-six percent of Stage III patients received chemotherapy. Median dose was 70 Gy (45-74 Gy) and fraction size ranged from 1.5-2.7 Gy. Median follow-up was 12 months, median OS was 22 months (95% CI 19-30 months), and LRC at two years was 69%. Fourteen local and eight regional events were scored with two CTVretro failures equating to a two-year CTV failure-free survival of 98%. CONCLUSION: Omission of a 1 cm CTV expansion appears feasible based on only two events among 110 patients and should be considered in radiation planning.

Image guided radiation therapy may result in improved local control in locally advanced lung cancer patients.

PURPOSE: Image guided radiation therapy (IGRT) is designed to ensure accurate and precise targeting, but whether improved clinical outcomes result is unknown. METHODS AND MATERIALS: A retrospective comparison of locally advanced lung cancer patients treated with and without IGRT from 2001 to 2012 was conducted. Median local failure-free survival (LFFS), regional, locoregional failure-free survival (LRFFS), distant failure-free survival, progression-free survival, and overall survival (OS) were estimated. Univariate and multivariate models assessed the association between patient- and treatment-related covariates and local failure. RESULTS: A total of 169 patients were treated with definitive radiation therapy and concurrent chemotherapy with a median follow-up of 48 months in the IGRT cohort and 96 months in the non-IGRT cohort. IGRT was used in 36% (62 patients) of patients. OS was similar between cohorts (2-year OS, 47% vs 49%, P = .63). The IGRT cohort had improved 2-year LFFS (80% vs 64%, P = .013) and LRFFS (75% and 62%, P = .04). Univariate analysis revealed IGRT and treatment year improved LFFS, whereas group stage, dose, and positron emission tomography/computed tomography planning had no impact. IGRT remained significant in the multivariate model with an adjusted hazard ratio of 0.40 (P = .01). Distant failure-free survival (58% vs 59%, P = .67) did not differ significantly. CONCLUSION: IGRT with daily cone beam computed tomography confers an improvement in the therapeutic ratio relative to patients treated without this technology.

Reirradiation for second primary or recurrent cancers of the head and neck: Dosimetric and outcome analysis.

BACKGROUND: The purpose of this study was to examine outcomes, toxicity, and dosimetric characteristics of patients treated with reirradiation for head and neck cancers. METHODS: Fifty patients underwent ≥2 courses of radiation therapy (RT) postoperatively or definitively with or without chemotherapy. Composite dose volume histograms (DVHs) for selected anatomic structures were correlated with grade ≥3 late toxicity. RESULTS: Median initial and retreatment radiation dose was 64 and 60 Gy, respectively. Median overall survival (OS), progression-free survival (PFS), and 1-year PFS rates were 18 months, 11 months, and 45%, respectively, with 13 months median follow-up. Thirty-four percent of patients experienced grade ≥3 late toxicity with 1 death from carotid blowout. The DVH corresponding to the carotid blowout fell above the third quartile compared with other patients. CONCLUSION: Our analysis is the first to systematically evaluate the dose to the carotid artery using composite dosimetry in head and neck reirradiation patients, and demonstrates a promising technique for evaluating the dose to other normal tissue structures. © 2015 Wiley Periodicals, Inc. Head Neck 38: E961-E969, 2016.

Genomic predictors of patterns of progression in glioblastoma and possible influences on radiation field design.

We present a retrospective investigation of the role of genomics in the prediction of central versus marginal disease progression patterns for glioblastoma (GBM). Between August 2000 and May 2010, 41 patients with GBM and gene expression and methylation data available were treated with radiotherapy with or without concurrent temozolomide. Location of disease progression was categorized as within the high dose (60 Gy) or low dose (46 Gy) volume. Samples were grouped into previously described TCGA genomic groupings: Mesenchymal (m), classical (c), proneural (pn), and neural (n); and were also classified by MGMT-Methylation status and G-Cimp methylation phenotype. Genomic groupings and methylation status were investigated as a possible predictor of disease progression in the high dose region, progression in the low dose region, and time to progression. Based on TCGA category there was no difference in OS (p = 0.26), 60 Gy progression (PN: 71 %, N: 60 %, M: 89 %, C: 83 %, p = 0.19), 46 Gy progression (PN: 57 %, N: 40 %, M: 61 %,C: 50 %, p = 0.8) or time to progression (PN: 9 months, N:15 months, M: 9 months, C: 7 months, p = 0.58). MGMT methylation predicted for improved OS (median 25 vs. 13 months, p = 0.01), improved DFS (median 13 vs. 8 months, p = 0.007) and decreased 60 Gy (p = 0.003) and 46 Gy (p = 0.006) progression. There was a cohort of MGMT methylated patients with late marginal disease progression (4/22 patients, 18 %). TCGA groups demonstrated no difference in survival or progression patterns. MGMT methylation predicted for a statistically significant decrease in in-field and marginal disease progression. There was a cohort of MGMT methylated patients with late marginal progression. Validations of these findings would have implications that could affect radiation field size.

Impact of systemic targeted agents on the clinical outcomes of patients with brain metastases.

BACKGROUND: To determine the clinical benefits of systemic targeted agents across multiple histologies after stereotactic radiosurgery (SRS) for brain metastases. METHODS: Between 2000 and 2013, 737 patients underwent upfront SRS for brain metastases. Patients were stratified by whether or not they received targeted agents with SRS. 167 (23%) received targeted agents compared to 570 (77%) that received other available treatment options. Time to event data were summarized using Kaplan-Meier plots, and the log rank test was used to determine statistical differences between groups. RESULTS: Patients who received SRS with targeted agents vs those that did not had improved overall survival (65% vs. 30% at 12 months, p < 0.0001), improved freedom from local failure (94% vs 90% at 12 months, p = 0.06), improved distant failure-free survival (32% vs. 18% at 12 months, p = 0.0001) and improved freedom from whole brain radiation (88% vs. 77% at 12 months, p = 0.03). Improvement in freedom from local failure was driven by improvements seen in breast cancer (100% vs 92% at 12 months, p < 0.01), and renal cell cancer (100% vs 88%, p = 0.04). Multivariate analysis revealed that use of targeted agents improved all cause mortality (HR = 0.6, p < 0.0001). CONCLUSIONS: Targeted agent use with SRS appears to improve survival and intracranial outcomes.

Comparison of clinical outcomes and genomic characteristics of single focus and multifocal glioblastoma.

We investigate the differences in molecular signature and clinical outcomes between multiple lesion glioblastoma (GBM) and single focus GBM in the modern treatment era. Between August 2000 and May 2010, 161 patients with GBM were treated with modern radiotherapy techniques. Of this group, 33 were considered to have multiple lesion GBM (25 multifocal and 8 multicentric). Patterns of failure, time to progression and overall survival were compared based on whether the tumor was considered a single focus or multiple lesion GBM. Genomic groupings and methylation status were also investigated as a possible predictor of multifocality in a cohort of 41 patients with available tissue for analysis. There was no statistically significant difference in overall survival (p < 0.3) between the multiple lesion tumors (8.2 months) and single focus GBM (11 months). Progression free survival was superior in the single focus tumors (7.1 months) as compared to multi-focal (5.6 months, p = 0.02). For patients with single focus, multifocal and multicentric GBM, 81, 76 and 88 % of treatment failures occurred in the 60 Gy volume (p < 0.5), while 54, 72, and 38 % of treatment failures occurred in the 46 Gy volume (p < 0.4). Out of field failures were rare in both single focus and multiple foci GBM (7 vs 3 %). Genomic groupings and methylation status were not found to predict for multifocality. Patterns of failure, survival and genomic signatures for multiple lesion GBM do not appreciably differ when compared to single focus tumors.

Taste and smell disturbances after brain irradiation: a dose-volume histogram analysis of a prospective observational study.

PURPOSE: Radiation-induced taste and smell disturbances are prevalent in patients receiving brain radiation therapy, although the mechanisms underlying these toxicities are poorly understood. We report the results of a single institution prospective clinical trial aimed at correlating self-reported taste and smell disturbances with radiation dose delivered to defined areas within the brain and nasopharynx. METHODS AND MATERIALS: Twenty-two patients with gliomas were enrolled on a prospective observational trial in which patients underwent a validated questionnaire assessing taste and smell disturbances at baseline and at 3 and 6 weeks after commencement of brain radiation therapy. Fourteen patients with glioblastoma, 3 patients with grade 3 gliomas, and 5 patients with low grade gliomas participated. Median dose to tumor volume was 60 Gy (range, 45-60 Gy). Dose-volume histogram (DVH) analysis was performed for specific regions of interest that were considered potential targets of radiation damage, including the thalamus, temporal lobes, nasopharynx, olfactory groove, frontal pole, and periventricular stem cell niche. The %v10 (percent of region of interest receiving 10 Gy), %v40, and %v60 were calculated for each structure. Data from questionnaires and DVH were analyzed using stepwise regression. RESULTS: Twenty of 22 patients submitted evaluable questionnaires that encompassed at least the entire radiation therapy course. Ten of 20 patients reported experiencing some degree of smell disturbance during radiation therapy, and 14 of 20 patients experienced taste disturbances. Patients reporting more severe taste toxicity also reported more severe toxicities with sense of smell (r(2) = 0.60, P < .006). Tumor location in the temporal lobe predicted for increased severity of taste toxicity (F3, 16 = 1.44, P < .06). The nasopharynx was the only structure in which the DVH data predicted the presence of radiation-induced taste changes (r(2) = 0.28, P < .02). CONCLUSIONS: Radiation-induced taste toxicity appears to be more common in temporal lobe tumors, and may be related to the dose received by the nasopharynx.

Management of mediastinal relapse after treatment with stereotactic body radiotherapy or accelerated hypofractionated radiotherapy for stage I/II non-small-cell lung cancer.

PURPOSE/OBJECTIVE(S): Regional failures occur in up to 15% of patients treated with stereotactic body radiotherapy (SBRT) for stage I/II lung cancer. This report focuses on the management of the unique scenario of isolated regional failures. METHODS: Patients treated initially with SBRT or accelerated hypofractionated radiotherapy were screened for curative intent treatment of isolated mediastinal failures (IMFs). Local control, regional control, progression-free survival, and distant control were estimated from the date of salvage treatment using the Kaplan-Meier method. RESULTS: Among 160 patients treated from 2002 to 2012, 12 suffered IMF and were amenable to salvage treatment. The median interval between treatments was 16 months (2-57 mo). Median salvage dose was 66 Gy (60-70 Gy). With a median follow-up of 10 months, the median overall survival was 15 months (95% confidence interval, 5.8-37 mo). When estimated from original treatment, the median overall survival was 38 months (95% confidence interval, 17-71 mo). No subsequent regional failures occurred. Distant failure was the predominant mode of relapse following salvage for IMF with a 2-year distant control rate of 38%. At the time of this analysis, three patients have died without recurrence while four are alive and no evidence of disease. High-grade toxicity was uncommon. CONCLUSIONS: To our knowledge, this is first analysis of salvage mediastinal radiation after SBRT or accelerated hypofractionated radiotherapy in lung cancer. Outcomes appear similar to stage III disease at presentation. Distant failures were common, suggesting a role for concurrent or sequential chemotherapy. A standard full course of external beam radiotherapy is advisable in this unique clinical scenario.

Thoracic re-irradiation using stereotactic body radiotherapy (SBRT) techniques as first or second course of treatment.

BACKGROUND AND PURPOSE: Management for in-field failures after thoracic radiation is poorly defined. We evaluated SBRT as an initial or second course of treatment re-irradiating in a prior high dose region. MATERIALS AND METHODS: Thirty-three patients were treated with re-irradiation defined by the prior 30 Gy isodose line. Kaplan-Meier estimates were performed for local (LC), regional (RC), distant control (DC), and overall survival (OS). The plans when available were summed to evaluate doses to critical structures. Patient and treatment variables were analyzed on UVA for the impact on control and survival measures. RESULTS: Median follow-up was 17 months. Treatment for sequential courses was as follows: (course1:course2) EBRT:SBRT (24 patients), SBRT:SBRT (7 patients), and SBRT:EBRT (3 patients). Median re-irradiation dose and fractionation was 50 Gy and 10 fractions (fx), with a median of 18 months (6-61) between treatments. Median OS was 21 months and 2 year LC 67%, yet LC for >1 fraction was 88% (p=0.006 for single vs. multiple). 10 patients suffered chronic grade 2-3 toxicity (6 chest wall pain, 3 dyspnea, 1 esophagitis) and 1 grade 5 toxicity with aorta-esophageal fistula after 54 Gy in 3 fx for a central tumor with an estimated EQD2 to the aorta of 200 Gy. CONCLUSION: Tumor control can be established with re-irradiation using SBRT techniques for in-field thoracic failures at the cost of manageable toxicity.

Limited margins using modern radiotherapy techniques does not increase marginal failure rate of glioblastoma.

OBJECTIVE: We investigate the patterns of failure in the treatment of glioblastoma (GBM) based on clinical target volume (CTV) margin size, dose delivered to the site of initial failure, and the use of temozolomide and intensity-modulated radiotherapy (IMRT). METHODS: Between August 2000 and May 2010, 161 patients with GBM were treated with radiotherapy with or without concurrent temozolomide. Patients were treated with CTV expansions that ranged from 5 to 20 mm using a shrinking field technique. Patterns of failure and time to progression and overall survival were compared based on CTV margin, use of temozolomide, and use of IMRT. Kaplan Meier analysis was used to estimate survival times, and χ test was used for comparison of cohorts. RESULTS: For patients treated with 5-, 10-, and 15- to 20-mm CTV, 79%, 77%, and 86% experienced failures in the 60 Gy volume, respectively. Forty-eight percent, 55%, and 66% of patients with 5-, 10-, and 15- to 20-mm CTV experienced failures in the 46 Gy volume, respectively. There was no statistical difference between patients treated with 5-, 10-, 15- to 20-mm margins with regard to 60 Gy failure (P=0.76), 46 Gy failure (P=0.51), or marginal failure (P=0.73). Eighty percent of patients receiving temozolomide experienced failures in the 60 Gy volume. There was no increased likelihood of marginal failures in patients receiving IMRT (P=0.97). CONCLUSIONS: Modern treatment techniques including use of concurrent temozolmide, limited CTV margin size, and IMRT have not greatly changed the patterns of failure of GBM.

Neuroanatomical target theory as a predictive model for radiation-induced cognitive decline.

OBJECTIVE: In a retrospective review to assess neuroanatomical targets of radiation-induced cognitive decline, dose volume histogram (DVH) analyses of specific brain regions of interest (ROI) are correlated to neurocognitive performance in 57 primary brain tumor survivors. METHODS: Neurocognitive assessment at baseline included Trail Making Tests A/B, a modified Rey-Osterreith Complex Figure, California or Hopkins Verbal Learning Test, Digit Span, and Controlled Oral Word Association. DVH analysis was performed for multiple neuroanatomical targets considered to be involved in cognition. The %v10 (percent of ROI receiving 10 Gy), %v40, and %v60 were calculated for each ROI. Factor analysis was used to estimate global cognition based on a summary of performance on individual cognitive tests. Stepwise regression was used to determine which dose volume predicted performance on global factors and individual neurocognitive tests for each ROI. RESULTS: Regions that predicted global cognitive outcomes at doses <60 Gy included the corpus callosum, left frontal white matter, right temporal lobe, bilateral hippocampi, subventricular zone, and cerebellum. Regions of adult neurogenesis primarily predicted cognition at %v40 except for the right hippocampus which predicted at %v10. Regions that did not predict global cognitive outcomes at any dose include total brain volume, frontal pole, anterior cingulate, right frontal white matter, and the right precentral gyrus. CONCLUSIONS: Modeling of radiation-induced cognitive decline using neuroanatomical target theory appears to be feasible. A prospective trial is necessary to validate these data.

A phase I study of gefitinib with concurrent dose-escalated weekly docetaxel and conformal three-dimensional thoracic radiation followed by consolidative docetaxel and maintenance gefitinib for patients with stage III non-small cell lung cancer.

BACKGROUND: Concurrent radiation and chemotherapy is the standard of care for good performance status patients with stage III non-small cell lung cancer. Locoregional control remains a significant factor relating to poor outcome. Preclinical and early clinical data suggest that docetaxel and gefitinib have radiosensitizing activity. This study sought to define the maximum tolerated dose of weekly docetaxel that could be given with daily gefitinib and concurrent thoracic radiation therapy. PATIENTS AND MATERIALS: Patients with histologically confirmed, inoperable stage III non-small cell lung cancer and good performance status (Eastern Cooperative Oncology Group 0-1) were eligible for this study. Patients received three-dimensional conformal thoracic radiation to a dose of 70 Gy concurrently with oral gefitinib at a dose of 250 mg daily and intravenous, weekly docetaxel at escalating doses from 15 to 30 mg/m2 in cohorts of patients. Patients were given a 2-week rest period after the concurrent therapy, during which they received only gefitinib. After the 2-week rest period, patients received consolidation chemotherapy with docetaxel 75 mg/m2 given every 21 days for two cycles. Maintenance gefitinib was continued until disease progression or study completion. RESULTS: Sixteen patients were enrolled on the study between December 2003 and April 2007 with the following characteristics: median age, 64 years (range 43-79 years); M/F: 9/7; and performance status 0/1, 1/15. Dose-limiting pulmonary toxicity and esophagitis were encountered at a weekly docetaxel dose of 25 mg/m2, resulting in a maximum tolerated dose of 20 mg/m2/wk. Overall, grade 3/4 hematologic toxicity was observed in 27% of patients. Grade 3/4 esophageal and pulmonary toxicities were reported in 27% and 20% of patients, respectively. The overall response rate was 46%, and the median survival for all patients was 21 months. CONCLUSIONS: Concurrent thoracic radiation with weekly docetaxel and daily gefitinib is feasible but results in moderate toxicity. For further studies, the recommended weekly docetaxel dose for this chemoradiation regimen is 20 mg/m2.

Anniversary Paper: the role of medical physicists in developing stereotactic radiosurgery.

This article is a tribute to the pioneering medical physicists over the last 50 years who have participated in the research, development, and commercialization of stereotactic radiosurgery (SRS) and stereotactic radiotherapy utilizing a wide range of technology. The authors have described the evolution of SRS through the eyes of physicists from its beginnings with the Gamma Knife in 1951 to proton and charged particle therapy; modification of commercial linacs to accommodate high precision SRS setups; the multitude of accessories that have enabled fine tuning patients for relocalization, immobilization, and repositioning with submillimeter accuracy; and finally the emerging technology of SBRT. A major theme of the article is the expanding role of the medical physicist from that of advisor to the neurosurgeon to the current role as a primary driver of new technology that has already led to an adaptation of cranial SRS to other sites in the body, including, spine, liver, and lung. SRS continues to be at the forefront of the impetus to provide technological precision for radiation therapy and has demonstrated a host of downstream benefits in improving delivery strategies for conventional therapy as well. While this is not intended to be a comprehensive history, and the authors could not delineate every contribution by all of those working in the pursuit of SRS development, including physicians, engineers, radiobiologists, and the rest of the therapy and dosimetry staff in this important and dynamic radiation therapy modality, it is clear that physicists have had a substantial role in the development of SRS and theyincreasingly play a leading role in furthering SRS technology.

Radiation safety issues with positron-emission/computed tomography simulation for stereotactic body radiation therapy.

Stereotactic body radiation therapy (SBRT) simulations using a Stereotactic Body Frame (SBF: Elekta, Stockholm, Sweden) were expanded to include 18F-deoxyglucosone positron-emission tomography (FDG PET) for treatment planning. Because of the length of time that staff members are in close proximity to the patient, concerns arose over the radiation safety issues associated with these simulations. The present study examines the radiation exposures of the staff performing SBRT simulations, and provides some guidance on limiting staff exposure during these simulations. Fifteen patients were simulated with PET/CT using the SBF. Patients were immobilized in the SBF before the FDG was administered. The patients were removed from the frame, injected with FDG, and allowed to uptake for approximately 45 minutes. After uptake, the patients were repositioned in the SBF. During the repositioning, exposure rates were recorded at the patient's surface, at the SBF surface, and at 15 cm, 30 cm, and 1 m from the SBF. Administered dose and the approximate time spent on patient repositioning were also recorded. The estimated dose to staff was compared with the dose to staff performing conventional diagnostic PET studies. The average length of time spent in close proximity (<50 cm) to the patient after injection was 11.7 minutes, or more than twice the length of time reported for diagnostic PET staff. That time yielded an estimated average dose to the staff of 26.5 microSv per simulation. The annual occupational exposure limit is 50 mSv. Based on dose per simulation, staff would have to perform nearly 1900 SBRT simulations annually to exceed the occupational limit. Therefore, at the current rate of 50-100 simulations annually, the addition of PET studies to SBRT simulations is safe for our staff. However, ALARA ("as low as reasonably achievable") principles still require some radiation safety considerations during SBRT simulations. The PET/CT-based SBRT simulations are safe and important for treatment planning that optimizes biologic dose distribution with highly accurate and reproducible target definition.

Photon spectral characteristics of dissimilar 6 MV linear accelerators.

This work measures and compares the energy spectra of four dosimetrically matched 6 MV beams, generated from four physically different linear accelerators. The goal of this work is twofold. First, this study determines whether the spectra of dosimetrically matched beams are measurably different. This study also demonstrates that the spectra of clinical photon beams can be measured as a part of the beam data collection process for input to a three-dimensional (3D) treatment planning system. The spectra of 6 MV beams that are dosimetrically matched for clinical use were studied to determine if the beam spectra are similarly matched. Each of the four accelerators examined had a standing waveguide, but with different physical designs. The four accelerators were two Varian 2100C/Ds (one 6 MV/18 MV waveguide and one 6 MV/10 MV waveguide), one Varian 600 C with a vertically mounted waveguide and no bending magnet, and one Siemens MD 6740 with a 6 MV/10 MV waveguide. All four accelerators had percent depth dose curves for the 6 MV beam that were matched within 1.3%. Beam spectra were determined from narrow beam transmission measurements through successive thicknesses of pure aluminum along the central axis of the accelerator, made with a graphite Farmer ion chamber with a Lucite buildup cap. An iterative nonlinear fit using a Marquardt algorithm was used to find each spectrum. Reconstructed spectra show that all four beams have similar energy distributions with only subtle differences, despite the differences in accelerator design. The measured spectra of different 6 MV beams are similar regardless of accelerator design. The measured spectra show excellent agreement with those found by the auto-modeling algorithm in a commercial 3D treatment planning system that uses a convolution dose calculation algorithm. Thus, beam spectra can be acquired in a clinical setting at the time of commissioning as a part of the routine beam data collection.