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Introduction: Distant metastases (DMs) are the primary driver of mortality for patients with early stage NSCLC receiving stereotactic body radiation therapy (SBRT), yet patient-level risk is difficult to predict. We developed and validated a model to predict individualized risk of DM in this population., Methods: We used a multi-institutional database of 1280 patients with cT1-3N0M0 NSCLC treated with SBRT from 2006 to 2015 for model development and internal validation. A Fine and Gray (FG) regression model was built to predict 1-year DM risk and compared with a random survival forests model. The higher performing model was evaluated on an external data set of 130 patients from a separate institution. Discriminatory performance was evaluated using the time-dependent area under the curve (AUC). Calibration was assessed graphically and with Brier scores., Results: The FG model yielded an AUC of 0.71 (95% confidence interval [CI]: 0.57-0.86) compared with the AUC of random survival forest at 0.69 (95% CI: 0.63-0.85) in the internal test set and was selected for further testing. On external validation, the FG model yielded an AUC of 0.70 (95% CI: 0.57-0.83) with good calibration (Brier score: 0.08). The model identified a high-risk patient subgroup with greater 1-year DM rates in the internal test (20.0% [3 of 15] versus 2.9% [7 of 241], p = 0.001) and external validation (21.4% [3 of 15] versus 7.8% [9 of 116], p = 0.095). A model nomogram and online application was made available., Conclusions: We developed and externally validated a practical model that predicts DM risk in patients with NSCLC receiving SBRT which may help select patients for systemic therapy., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: Although stereotactic body radiation therapy (SBRT) is the standard of care for inoperable early-stage non-small cell lung carcinoma (NSCLC), its role for medically operable patients remains controversial. To address this knowledge gap, we conducted a multi-institutional study to assess post-SBRT disease control and survival outcomes in medically operable patients., Methods: We conducted a retrospective cohort study including patients with biopsy-proven cT1-2N0M0 NSCLC treated with definitive SBRT (2006-2015). Per patient charts, inoperability referred to documentation of poor surgical candidacy with a given rationale for lack of resection. Charts of operable patients contained documentation of patients refusing surgery or choosing SBRT, without a documented rationale for inoperability. Subjects were excluded in cases of ambiguity regarding the aforementioned definitions and/or lack of clearly documented operability status. Endpoints included local failure (LF) and regional-distant failure, both evaluated with Fine and Gray competing risks regression; Kaplan-Meier methodology analyzed overall survival (OS) and progression-free survival (PFS)., Results: Of 952 patients, 408 (42.9%) were operable, and 544 (57.1%) were inoperable. Median follow-up was 22 months. Two-year LF was 9.7% in operable patients and 8.2% in inoperable patients (p = 0.36). There was no statistical difference in regional-distant failure (p = 0.55) between cohorts. Operable patients experienced statistically higher OS (p = 0.04), but not PFS (p = 0.11). Respective 1-, 2-, and 3-year OS in operable patients were 85.4%, 66.2%, and 51.2%., Conclusions: Although patients with operable NSCLC experience higher OS than their inoperable counterparts, disease-related outcomes are similar. These results may better inform shared decision-making between medically operable patients and their multidisciplinary providers., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: Although adjuvant systemic therapy (ST) is often recommended for the treatment of patients with high-risk, early-stage non-small cell lung carcinoma (NSCLC) after surgery, there is little evidence supporting the use of ST with stereotactic body radiotherapy (SBRT)., Methods: We conducted a retrospective cohort study using a multi-institutional database to identify consecutive patients with T1-3N0M0 NSCLC treated with definitive SBRT from 2006-2015. Treatment groups were defined as those who received SBRT + ST or SBRT alone. Regional-distant failure (RDF) was analyzed with Fine and Gray competing risks regression. Progression-free (PFS) and overall survival (OS) were analyzed with the Kaplan-Meier method and Cox regression. Additional comparisons were made after 2:1 nearest-neighbor propensity-score matching on clinical risk factors., Results: We identified 54 patients who received SBRT + ST. The most common ST regimen was a platinum doublet (n = 38; 70.4%). Compared with patients receiving SBRT (n = 1269), SBRT + ST patients were younger (median age: 70 v 77 years, p < 0.001), had larger tumors (>3 cm: 38.9% v 21.6%, p = 0.02) and higher T-stage (T2-3: 42.6% v 22.5%, p = 0.002). Compared with SBRT patients, SBRT + ST patients had lower 2-year RDF (3.1% v 16.9%, p = 0.02). On multivariable analysis, SBRT + ST was associated with reduced RDF (HR: 0.15, 95%CI: 0.04-0.62), with a trend toward improved PFS (HR: 0.70, 95%CI: 0.48-1.03), but not OS (HR: 0.74, 95%CI: 0.49-1.11). After propensity-score matching, the SBRT + ST cohort demonstrated improved RDF (HR: 0.17, 95%CI: 0.04-0.76) and PFS (HR: 0.59, 95%CI: 0.38-0.93)., Conclusion: In this multi-institutional analysis, adjuvant ST was independently associated with reduced RDF in early-stage NSCLC patients treated with SBRT., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: Adjuvant radiation therapy (RT) for breast cancer improves outcomes, but prior studies have documented substantive cardiac dose and cardiac risk. We assessed the mean heart dose (MHD) of RT and estimated the risk of RT-associated cardiac toxicity in women undergoing adjuvant RT for breast cancer in contemporary (predominantly) community practice., Methods and Materials: We identified women with left-sided breast cancer receiving adjuvant RT between 2012 and 2014 from 94 centers across 16 states. We used bivariate analyses and multivariable linear regression to assess associations between RT techniques and MHD. Excess RT-related cardiac risk by age 80 was estimated for women diagnosed at age 60 using the previously reported relationship between MHD and cardiac risk., Results: Among 1161 women, 77.3% were treated in community practice and with breast conservation (77.8%). The most common techniques were free-breathing (92.2%), supine (94.8%), and fixed gantry intensity modulated RT (FG-IMRT; 46.9%). The median MHD was 2.76 Gy (interquartile range, 1.47-5.03). In multivariable analyses, the predicted median MHD with deep inspiration breath hold was 2.41 Gy compared with 3.86 Gy with free-breathing (P < .001). Three-dimensional conformal RT (3D-CRT) was associated with a lower predicted median MHD (2.78 Gy) than FG-IMRT (4.02 Gy) or rotational IMRT, 6.60 Gy, P < .001). For 60-year-old women with the median MHD of the study population (2.76 Gy) and no cardiovascular risk factors, the 20-year predicted excess risk of death from ischemic heart disease attributable to radiation was 3.5 excess events/1000 patients, in contrast to estimates of 8 events/1000 from prior analyses. The predicted risk of cardiac events varied based on radiation technique, with 4 excess events/1000 with 3D-CRT, 5 excess events/1000 with FG-IMRT, and 8 excess events/1000 with rotational IMRT., Conclusions: MHD varies substantially across patients and is influenced by technique in predominantly community settings. Overall risk of cardiac toxicity is modest., (Copyright © 2017 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Purpose: To analyze the relationship between angle number and mean heart dose (MHD) in adjuvant fixed gantry intensity modulated radiation therapy (FG-IMRT) treatment of left-sided breast cancer as is currently practiced in the community., Methods and Materials: We performed a retrospective, multi-institutional review of women with left-sided breast cancer receiving adjuvant FG-IMRT between 2012 and 2014, encompassing 85 centers in 15 states. Bivariate and multivariate regression analyses were done to identify factors associated with MHD. Long-term cardiac risk was estimated according to a previously published model., Results: Of the 538 women included, 284 had >2 gantry angle treatment plans (multi-angle), and 254 had 2 gantry angle (standard) plans. Median MHD was higher in patients with multi-angle plans compared with standard (median 475 vs 203 cGy). Number of gantry angles was significantly associated with MHD, with multi-angle plans independently increasing MHD by 229 cGy. Absolute risk of acute coronary events 20 years after treatment was estimated as 7 excess events per 1000 women for standard plans, compared with 12 excess events for multi-angle plans., Conclusions: Fixed gantry IMRT breast treatment plans with >2 gantry angles were associated with increased MHD, which translated to an increased cardiac risk. Clinicians should account for this potential drawback in treatment technique when assessing overall plan quality., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To determine the effect of biologically effective dose (BED 10 ) and radiation treatment schedule on overall survival (OS) in patients with early-stage non-small cell lung cancer (NSCLC) undergoing stereotactic body radiation therapy (SBRT)., Methods and Materials: Using data from 65 treatment centers in the United States, we retrospectively reviewed the records of T1-2 N0 NSCLC patients undergoing SBRT alone from 2006 to 2014. Biologically relevant covariates, including dose per fraction, number of fractions, and time between fractions, were used to quantify BED 10 and radiation treatment schedule. The linear-quadratic equation was used to calculate BED 10 and to generate a dichotomous dose variable of <105 Gy versus ≥105 Gy BED 10 . The primary outcome was OS. We used the Kaplan-Meier method, the log-rank test, and Cox proportional hazards regression with propensity score matching to determine whether prescription BED 10 was associated with OS., Results: We identified 747 patients who met inclusion criteria. The median BED 10 was 132 Gy, and 59 (7.7%) had consecutive-day fractions. Median follow-up was 41 months, and 452 patients (60.5%) had died by the conclusion of the study. The 581 patients receiving ≥105 Gy BED 10 had a median survival of 28 months, whereas the 166 patients receiving <105 Gy BED 10 had a median survival of 22 months (log-rank, P=.01). Radiation treatment schedule was not a significant predictor of OS on univariable analysis. After adjusting for T stage, sex, tumor histology, and Eastern Cooperative Oncology Group performance status, BED 10 ≥105 Gy versus <105 Gy remained significantly associated with improved OS (hazard ratio 0.78, 95% confidence interval 0.62-0.98, P=.03). Propensity score matching on imbalanced variables within high- and low-dose cohorts confirmed a survival benefit with higher prescription dose., Conclusions: We found that dose escalation to 105 Gy BED 10 and beyond may improve survival in NSCLC patients treated with SBRT., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background and Purpose: Evaluate changes in bowel, urinary and sexual patient-reported quality of life following treatment with moderately hypofractionated radiotherapy (<5Gray/fraction) or stereotactic body radiation therapy (SBRT;5-10Gray/fraction) for prostate cancer., Materials and Methods: In a pooled multi-institutional analysis of men treated with moderate hypofractionation or SBRT, we compared minimally detectable difference in bowel, urinary and sexual quality of life at 1 and 2years using chi-squared analysis and logistic regression., Results: 378 men received moderate hypofractionation compared to 534 men who received SBRT. After 1year, patients receiving moderate hypofractionation were more likely to experience worsening in bowel symptoms (39.5%) compared to SBRT (32.5%; p=.06), with a larger difference at 2years (37.4% versus 25.3%, p=.002). Similarly, patients receiving moderate fractionation had worsening urinary symptom score compared to patients who underwent SBRT at 1 and 2years (34.7% versus 23.1%, p<.001; and 32.8% versus 14.0%, p<.001). There was no difference in sexual symptom score at 1 or 2years. After adjusting for age and cancer characteristics, patients receiving SBRT were less likely to experience worsening urinary symptom scores at 2years (odds ratio: 0.24[95%CI: 0.07-0.79])., Conclusions: Patients who received SBRT or moderate hypofractionation have similar patient-reported change in bowel and sexual symptoms, although there was worse change in urinary symptoms for patients receiving moderate hypofractionation., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: The American Society for Radiation Oncology (ASTRO) Physics Core Curriculum Subcommittee (PCCSC) has updated the recommended physics curriculum for radiation oncology resident education to improve consistency in teaching, intensity, and subject matter., Methods and Materials: The ASTRO PCCSC is composed of physicists and physicians involved in radiation oncology residency education. The PCCSC updated existing sections within the curriculum, created new sections, and attempted to provide additional clinical context to the curricular material through creation of practical clinical experiences. Finally, we reviewed the American Board of Radiology (ABR) blueprint of examination topics for correlation with this curriculum., Results: The new curriculum represents 56 hours of resident physics didactic education, including a 4-hour initial orientation. The committee recommends completion of this curriculum at least twice to assure both timely presentation of material and re-emphasis after clinical experience. In addition, practical clinical physics and treatment planning modules were created as a supplement to the didactic training. Major changes to the curriculum include addition of Fundamental Physics, Stereotactic Radiosurgery/Stereotactic Body Radiation Therapy, and Safety and Incidents sections, and elimination of the Radiopharmaceutical Physics and Dosimetry and Hyperthermia sections. Simulation and Treatment Verification and optional Research and Development in Radiation Oncology sections were also added. A feedback loop was established with the ABR to help assure that the physics component of the ABR radiation oncology initial certification examination remains consistent with this curriculum., Conclusions: The ASTRO physics core curriculum for radiation oncology residents has been updated in an effort to identify the most important physics topics for preparing residents for careers in radiation oncology, to reflect changes in technology and practice since the publication of previous recommended curricula, and to provide practical training modules in clinical radiation oncology physics and treatment planning. The PCCSC is committed to keeping the curriculum current and consistent with the ABR examination blueprint., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Despite improvements in surgical technique, radiation therapy delivery, and options for systemic cytotoxic therapy, the median survival for patients with newly diagnosed glioblastoma multiforme remains poor at 15 months with trimodality therapy. Multiple immunologic approaches are being tested to enhance the response of these tumors to existing therapy and/or to stimulate innate immune responses., Methods: We review the existing data that support the continued development of immunologic therapy in the treatment armamentarium against glioblastoma multiforme, with a focus on clinical data documenting outcomes., Results: In phase I and phase II trials, antitumor vaccines (dendritic and formalin-fixed) have demonstrated clinical efficacy with mild toxicity, suggesting that innate immune responses can be amplified and directed against these tumors. Suicide gene therapy (gene-mediated cytotoxic therapy) using a number of viral vectors and molecular pathways has also shown efficacy in completed phase I and ongoing phase II trials. In addition, neural stem cells are being investigated as vectors in this approach., Conclusions: Although phase III data are needed before immunologic therapies can be widely implemented into clinical practice, the existing phase I and phase II data suggest that these therapies can produce meaningful and sometimes durable responses in patients with glioblastoma multiforme with mild toxicity compared with other existing therapies.

Traditional treatment beams for non-small-cell lung cancer are limited to the axial plane. For many tumor geometries, non-axial orientations appear to reduce the dose to normal tissues (e.g. heart, liver). We hypothesize that non-axial beams provide a significant reduction in incidental irradiation of the heart and liver, while maintaining adequate target coverage. CT scans of twenty-four patients with lower lobe lung cancers were studied. For each patient, an opposed oblique axial beam pair and a competing non-axial opposed oblique pair were generated, both off-cord. The competing plans delivered comparable doses/margins to the GTV. DVHs and integral doses were computed for all structures of interest for the two competing plans. The integral dose was compared for axial and non-axial beams for each contoured organ using a paired t-test. Dose to the heart was significantly lower for the non-axial plans ( p = .0001). For 20/24 patients, the integral heart dose was reduced by using non-axial beams. In those patients with tumors located in the inferior right lower lobe, a lower dose to the liver was achieved when non-axial beams were used. There were no meaningful differences in dose to the GTV, lungs, or skin between axial and non-axial beams. Non-axial beams can reduce the dose to the heart and liver in patients with lower lobe lung cancers. Non-axial beams may be clinically beneficial in these patients and should be considered as an option during planning.

Purpose: A prospective study was performed to formally relate dose-dependent radiologically defined changes in normal brain induced by radiotherapy (RT) to neurocognitive dysfunction in subjects with primary brain tumors., Methods and Materials: Adult patients receiving three-dimensional RT for central nervous system (CNS) tumors were enrolled. Positron emission tomography (PET) scanning and neuropsychological testing were performed before RT and 3 weeks and 6 months after treatment. Analyses were performed for correlations between changes in 2-deoxy-2-[(18)F]-fluoro-d-glucose (FDG)-PET (metabolism), (15)O-PET (relative blood flow), regional radiation dose, follow-up time, and neuropsychological test scores., Results: Eleven subjects were enrolled and 6 completed follow-up studies. The PET data showed reduced FDG uptake, with average decreases of 2-6% in regions of the brain receiving greater than 40 Gy at 3 weeks' and 6 months' follow-up. The (15)O-H(2)O PET showed increases (<10%) at 3 weeks in relative regional blood flow in brain receiving greater than 30 Gy, but less at the 6-month follow-up studies. There were significant correlations between decreases in FDG uptake and increased scores from the Symptom Checklist-90-R, with an average increase in T score of 2 (p < 0.0001). The Wisconsin Card Sorting Test showed a significant correlation of decreased FDG uptake with increased errors and perseveration in test performance, with an average decrease in T score of 11 (p = 0.037)., Conclusions: A dose-dependent response of CNS tissue was detected using FDG PET in this small number of patients. Decreases in CNS metabolism correlated with decreased performance on neuropsychological tests for problem solving, cognitive flexibility, and global measures of psychopathology. Additional research is needed to verify and define these findings.

Purpose: Thalidomide has broad anticytokine properties, which might protect normal tissues in patients undergoing chemoradiotherapy. The purpose of this study was to determine the maximal tolerated dose of thalidomide when used in combination with vinorelbine plus thoracic radiotherapy., Methods and Materials: Eligible patients had inoperable Stage III non-small-cell lung cancer, a Karnofsky Performance Status>or=70, and life expectancy>or=6 months. Patients underwent pretreatment evaluation of lung function. Radiotherapy consisted of 66 Gy in 6.5 weeks. Vinorelbine was administered i.v. (5 mg/m2) 3 times per week just before radiotherapy. Thalidomide was begun at 50 mg, p.o., on day 1 of chemoradiotherapy and continued once daily for 6 months. Side effects were scored using National Cancer Institute Common Toxicity Criteria., Results: Ten patients were enrolled. Of the first 6 patients, 2 developed major thrombotic events that were believed to be possibly related to thalidomide. The study was suspended and modified to require prophylactic anticoagulation. Of the last 4 patients, 2 developed dose-limiting toxicity attributable to thalidomide; both patients required a dose reduction of thalidomide to <50 mg/day. Because the drug is not available in an oral product providing <50 mg/day, the study was closed., Conclusions: The combination of thalidomide concurrently with thoracic radiotherapy and vinorelbine resulted in excessive toxicity.

Objective: To determine the feasibility and maximum tolerated dose of dose-dense topotecan as induction chemotherapy before standard therapy (carboplatin plus etoposide alone or in combination with radiotherapy) in patients with small cell lung cancer (SCLC)., Patients and Methods: Chemotherapy-naive patients with SCLC and good performance status were eligible. Three 2-week cycles of dose-dense topotecan administered on days 1-3 with granulocyte colony-stimulating factor support were followed by four cycles of standard carboplatin plus etoposide therapy alone (extensive-stage SCLC) or with radiotherapy (limited-stage SCLC). The dose of topotecan was escalated from 1.5 mg/m2/day to 2.5 mg/m2/day in increments of 0.25 mg/m2/day within cohorts of 3-5 patients each. Dose-limiting toxicity was defined as any grade 3 or 4 toxicity resulting in a treatment reduction or a delay of >3 days., Results: Twenty-two patients with SCLC (5 limited-stage, 17 extensive-stage) were enrolled. Treatment was well tolerated. The dose-limiting toxicities were thrombocytopenia and neutropenia, and the maximum tolerated dose of dose-dense topotecan induction therapy was 2.25 mg/m2/day. Overall, topotecan-related grade 3/4 haematological toxicities included neutropenia (n = 4), thrombocytopenia (n = 3) and febrile neutropenia (n = 1). No grade 4 non-haematological toxicities occurred. Grade 3 adverse events included nausea (n = 2), renal toxicity (n = 1) and anorexia (n = 1). Toxicity during the carboplatin plus etoposide +/- radiotherapy phase of therapy was consistent with that reported in previous trials. The overall response rate was 80% for limited-stage and 76% for extensive-stage SCLC. Median survival was 8 months in patients with limited-stage SCLC and 13.5 months for patients with extensive-stage SCLC., Conclusion: The results of this phase I study suggest that a regimen of sequential dose-dense topotecan and carboplatin plus etoposide is feasible, and the preliminary activity observed in patients with SCLC warrants further investigation at a starting dose of topotecan 2.25 mg/m2/day.

Purpose: To assess the difficulty of assigning a definitive clinical diagnosis of radiation (RT)-induced lung injury in patients irradiated for lung cancer., Methods: Between 1991 and 2003, 318 patients were enrolled in a prospective study to evaluate RT-induced lung injury. Only patients with lung cancer who had a longer than 6-month follow-up (251 patients) were considered in the current analysis. Of these, 47 of 251 patients had Grade >/=2 (treated with steroids) increasing shortness of breath after RT, thought possibly consistent with pneumonitis/fibrosis. The treating physician, and one to three additional reviewing physicians, evaluated the patients or their medical records, or both. The presence or absence of confounding clinical factors that made the diagnosis of RT-induced uncertain lung injury were recorded., Results: Thirty-one of 47 patients (66%) with shortness of breath had "classic" pneumonitis, i.e., they responded to steroids and had a definitive diagnosis of pneumonitis. In 13 of 47 patients (28%), the diagnosis of RT-induced toxicity was confounded by possible infection; exacerbation of preexisting lung disease (chronic obstructive pulmonary disease); tumor regrowth/progression; and cardiac disease in 6, 8, 5, and 1 patients, respectively (some of the patients had multiple confounding factors and were counted more than once). An additional 3 patients (6%) had progressive shortness of breath and an overall clinical course more consistent with fibrosis. All 3 had evidence of bronchial stenosis by bronchoscopy., Conclusions: Scoring of radiation pneumonitis was challenging in 28% of patients treated for lung cancer owing to confounding medical conditions. Recognition of this uncertainty is needed and may limit our ability to understand RT-induced lung injury.

Purpose: Incidental esophageal irradiation during lung cancer therapy often causes morbidity. There is interest in trying to relate esophageal dosimetric parameters to the risk of injury. These parameters typically rely on CT-defined esophageal contours, and thus systematic limitations in esophageal contouring will influence these parameters. We herein assess the ability of a correction method, based on physiologic principles, to improve the predictive power of dosimetric parameters for radiation-induced esophageal injury., Methods and Materials: Esophageal contours for 236 patients treated for lung cancer were quantitatively analyzed. All patients received three-dimensional planning, and all contours were generated by the same physician on axial CT images. Traditional dose-volume histogram (DVH)-based dosimetric parameters were extracted from the three-dimensional data set. A second set of "anatomically correct" dosimetric parameters was derived by adjusting the contours to reflect the known shape of the esophagus. Each patient was scored for acute and late toxicity using ROTG criteria. Univariate analysis was used to assess the predictive power of corrected and uncorrected dosimetric parameters (e.g., mean dose, V(50), and V(60)) for toxicity. The p values were taken as a measure of their significance., Results: The univariate results indicate that both corrected and uncorrected dosimetric parameters are generally predictors for toxicity. The corrected parameters are more highly correlated (lower p value) with outcomes than the uncorrected metrics., Conclusions: The inclusion of corrections, based on anatomic realities, to DVH-based dosimetric parameters may provide dosimetric parameters that are better correlated with clinical outcomes than are traditional DVH-based metrics.

Purpose: To evaluate the clinical and three-dimensional dosimetric parameters associated with esophageal injury after radiotherapy (RT) for non-small-cell lung cancer., Methods and Materials: The records of 254 patients treated for non-small-cell lung cancer between 1992 and 2001 were reviewed. A variety of metrics describing the esophageal dose were extracted. The Radiation Therapy Oncology Group toxicity criteria for grading of esophageal injury were used. The median follow-up time for all patients was 43 months (range, 0.5-120 months). Logistic regression analysis, contingency table analyses, and Fisher's exact tests were used for statistical analysis., Results: Acute toxicity occurred in 199 (78%) of 254 patients. For acute toxicity of Grade 2 or worse, twice-daily RT, age, nodal stage of N2 or worse, and most dosimetric parameters were predictive. Late toxicity occurred in 17 (7%) of 238 patients. The median and maximal time to the onset of late toxicity was 5 and 40 months after RT, respectively. Late toxicity occurred in 2%, 3%, 17%, 26%, and 100% of patients with acute Grade 0, 1, 2, 3, and 4 toxicity, respectively. For late toxicity, the severity of acute toxicity was most predictive., Conclusion: A variety of dosimetric parameters are predictive of acute and late esophageal injury. A strong correlation between the dosimetric parameters prevented a comparison between the predictive abilities of these metrics. The presence of acute injury was the most predictive factor for the development of late injury. Additional studies to define better the predictors of RT-induced esophageal injury are needed.

Purpose: To assess the incidence of clinically significant bronchial stenosis in patients treated with high doses (i.e., >70 Gy) of twice-daily external beam radiation therapy (RT)., Methods and Materials: The outcomes of 103 patients with unresectable non-small-cell lung cancer, treated twice daily to doses ranging from 7080 to 8640 cGy between 1992 and 2001, were analyzed. Most were treated on prospective clinical trials. For the dose-effect comparison, the patients were divided on the basis of the total dose: 67 received 74 Gy (range, 70.8-74.5 Gy; median, 73.6 Gy), 20 received 80 Gy, and 16 received 86 Gy (range, 85.2-86.4 Gy; median, 86.4 Gy). Sixty-six patients received sequential chemotherapy before RT. RT-induced bronchial stenosis was defined as symptomatic airway narrowing diagnosed by bronchoscopy or computed tomography scan without evidence of recurrent tumor in that region., Results: Eight patients developed RT-induced, clinically significant, bronchial stenosis 2-48 months (median, 6 months) after RT. The 1-year and 4-year actuarial rate of stenosis was 7% and 38%, respectively. The median overall survival was 2.5 years (5 of 8 were alive at the writing of this report). A suggestion was also found of a dose-response effect with external beam radiotherapy-induced stenosis, with a rate of 4% and 25% at a dose of approximately 74 Gy and 86 Gy, respectively., Conclusion: Radiation therapy-induced bronchial stenosis is a significant clinical complication of dose escalation for lung cancer. This complication has been previously mentioned in the literature, but ours is the largest report to date, and the findings suggest that the risk rises with increasing dose. It is likely that this process would manifest in more patients if their disease were controlled well enough for more prolonged survival.

Purpose: To prospectively determine the maximum-tolerated dose of accelerated hyperfractionated conformal radiotherapy (RT; 1.6 Gy bid) for unresectable locally advanced lung cancer (IIB to IIIA/B) following induction carboplatin/paclitaxel (C/T) or carboplatin/vinorelbine (C/N)., Methods: Induction chemotherapy, C/T or C/N, was followed by escalating doses of conformally-planned RT (73.6 to 86.4 Gy in 6.4-Gy increments). Concurrent boost methods delivered 1.6 and 1.25 Gy bid to the gross and clinical target volumes, respectively., Results: Between November 1997 and February 2002, 44 patients were enrolled (median age, 59 years; 59% male; stage III, 98%; median tumor size, 4 cm). Thirty-nine patients completed induction chemotherapy: 19 had a partial response, seven progressed, 15 had no response, and three were not assessable. Chemotherapy-associated toxicities were similar in the two chemotherapy groups. The incidence of grade > or = 3 RT-induced toxicity was 1/13, 2/14, and 4/12 at 73.6, 80, and 86.4 Gy, respectively, thus defining the maximum tolerated dose at approximately 80 Gy. Toxicities were in both lung and esophagus and were similar in the two chemotherapy arms. With a median followup of 34 months in the survivors, the actuarial 2-year survival was 47%, the median survival was 18 months. Fifteen patients had tumor relapse: 5 local failures in the high-dose volume, 2 regional failures outside of the high-dose volume, and 8 distant metastases., Conclusion: High-dose conformal twice-daily radiation therapy to approximately 80 Gy appears tolerable in well-selected patients with unresectable lung cancer following either C/T or C/N. Dose-limiting toxicities are mainly pulmonary and esophageal.

The risk of lung injury is a significant limiting factor in the use of thoracic radiotherapy for lung cancer. Given the high mortality and local failure rates in patients with unresectable lung cancer, a goal has been to increase the dose to the tumor as much as possible while trying to limit the damage to normal tissue. Efforts have been made to predict the risks for lung injury pretreatment, based on the planned dose and volume of lung treated, with mixed results. Complicating factors include performance status, underlying medical conditions, possible genetic predisposition to injury, and tumor location-associated changes in lung function. Much as a thoracic surgeon stratifies a patient's risk for pulmonary morbidity before resection, radiation oncologists should perform an assessment of patient specific factors that will impact on the potential toxicity of a given course of treatment. We present a proposed approach to the evaluation, risk assessment, and follow-up of patients treated with thoracic radiotherapy for lung cancer.

Purpose: To report the incidence of late complications in long-term survivors of very-high-dose thoracic radiotherapy (RT) treated on a prospective clinical trial., Methods and Materials: Patients with locally advanced or medically inoperable non-small-cell lung cancer received three-dimensional conformal RT to the primary tumor and radiographically involved lymph nodes to a dose of 73.6 Gy at 1.6 Gy twice daily. If the plasma transforming growth factor-beta1 (TGF-beta1) level was normal after 73.6 Gy, additional twice-daily RT was delivered to successively higher total doses until the maximal tolerated dose was reached. Patients within a given dose level were followed for 6 months before escalation to the next dose level was permitted. Late complications were defined according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria., Results: Thirty-eight patients were enrolled between 1996 and 1999. Twenty-four patients were not eligible for radiation dose escalation beyond 73.6 Gy because of persistently abnormal TGF-beta1 levels. Fourteen patients received dose escalation (80 Gy in 8; 86.4 Gy in 6). Grade 3 or greater late complications occurred in 4 of 24, 1 of 8, and 2 of 6 patients treated to 73.6, 80, and 86.4 Gy, respectively. The corresponding patient numbers with late Grade 4-5 toxicity were 3 of 24, 0 of 6, and 0 of 8. Overall, 7 (18%) of the 38 patients developed Grade 3-5 late toxicity. Nonpulmonary complications predominated (4 of 7). Five (71%) of seven serious complications developed within 11 months after RT; however, the remaining two complications (29%) occurred very late (at 43 and 62 months). The 5-year actuarial risk of late Grade 3-5 complications was 33%., Conclusion: Long-term survivors of very-high-dose RT for non-small-cell lung cancer have a significant risk of severe treatment-related complications. At these high dose levels, the predominant toxicity may no longer be pulmonary. All Grade 4-5 complications occurred in patients whose dose was limited to 73.6 Gy because of a persistently elevated TGF-beta1. Thus, persistently elevated plasma TGF-beta1 levels toward the end of RT may identify patients at greatest risk of severe complications.

Purpose: To evaluate the long-term changes in pulmonary function tests (PFTs) in patients surviving at least 2 years after definitive radiotherapy (RT) for unresectable lung cancer., Methods and Materials: Between 1992 and 2000, 277 patients were enrolled in a prospective clinical study to relate RT-induced changes in lung function with dosimetric and functional metrics. Of these, 128 received definitive RT for lung cancer, and 13 of these had follow-up PFTs for approximately >/=2 years without evidence of recurrent or progressive cancer. PFTs were obtained before RT and approximately every 6 months after RT. The results were evaluated on the basis of each study's "percentage of predicted" of normal values (i.e., adjusted for age, gender, height), and a patient's sequential examinations were compared with their initial study and a percentage of the baseline value was calculated. Follow-up PFTs were available for a median of 38 months (range 23-95). The median patient age was 65 years (range 40-74), 6 patients were men, and 10 were white. Most had Stage T2-T4 and N2-N3. The median RT dose was 71.4 Gy (range 60-73), 6 had twice-daily RT. Four patients received chemotherapy, one concurrent and three neoadjuvant. None of the patients continued to smoke after their treatment. The median pre-RT PFT results were (percentage of predicted) forced expiratory volume in 1 s, 67% (range 24-121); forced vital capacity, 72% (range 45-116); and diffusing capacity of lung for carbon monoxide, 70% (range 41-129)., Results: At 6 months, all PFT values had declined, with some stabilization by 1 year. However, after 1 year, a gradual reduction occurred in all three parameters. Ten patients (77%) developed RT-induced respiratory symptoms (2 cough only, 8 dyspnea) at 2-21 months (median 5) after treatment. Two patients required inhalers, another required long-term steroids and oxygen. Of the 8 patients with dyspnea, 7 had an increase in symptoms beyond 2 years. No patient died of RT-induced pulmonary insufficiency., Conclusion: RT caused a decline in PFTs that was apparent at 6 months and continued well beyond 1 year. The continued decline in PFTs is suggestive of progressive/evolving RT-induced lung injury. "Late" pulmonary symptoms have also occurred in these patients. Because of the high mortality rate of unresectable lung cancer, few patients can be evaluated for long-term analysis. Additional studies and pooling of data from multiple institutions may help to clarify better the long-term impact of RT on pulmonary function in this subset of patients.

Purpose: To review the outcome of patients with limited-stage small-cell lung cancer receiving daily thoracic irradiation (RT) to approximately 60 Gy., Methods and Materials: The records of patients treated with RT for limited-stage small-cell lung cancer between 1991 and 1999 at Duke University were retrospectively reviewed. Sixty-five patients were identified who had received continuous course once-daily 1.8-2 Gy fractions to approximately 60 Gy (range 58-66). All patients received chemotherapy (CHT); 32 received concurrent RT/CHT and 33 sequential CHT and then RT. Prophylactic cranial RT was administered to 17 patients. The time from diagnosis to local failure, tumor progression, and death was assessed using actuarial methods. The median follow-up for all patients was 16.7 months and for surviving patients was 29.6 months. The median age was 64 years (range 36-83), and the median Karnofsky performance status was 80 (range 50-100)., Results: The 3-year actuarial rate of local failure, progression-free survival, and overall survival was 40%, 25%, and 23%, respectively. One case of acute Grade 3 esophagitis developed. Ten late complications occurred: four pulmonary, two esophageal, two infectious, one leukemia, and one retinal toxicity with prophylactic cranial RT. Six were mild and resolved with treatment., Conclusion: CHT plus approximately 60 Gy of once-daily RT for limited-stage small-cell lung cancer was generally well tolerated. The survival rates were less than have been reported using 45 Gy in 1.5-Gy twice-daily fractions (2-year overall survival rate 47% compared with 30% in this study), but may be comparable because fewer than one-half our patients received concurrent CHT/RT and only 26% received prophylactic cranial RT. The relatively low rate of normal tissue morbidity in our patients supports the use of conventional once-daily fractionation to > or = 60 Gy. A randomized trial would be required to compare the outcomes after maximally tolerated dose twice-daily RT vs. maximally tolerated dose daily RT.

A steepest-descent gradient algorithm is developed to optimize the stepping of a 90Sr/90Y radiation source train (RST) for intravascular brachytherapy (IVB). The objective function is to deliver a uniform dose in a coronary target vessel and minimize the dose in adjacent normal vessel tissue at the proximal and distal edges of the coronary target vessel. Based on the target length and number of dwell points (number of steps), the algorithm modulates the dwell times and corresponding dwell positions that optimize the weighted addition of staggered EGS4 Monte Carlo (MC) calculated dose distribution from a single RST. Stepping treatment plans are generated for target vessel lengths of 3.0, 3.3, and 3.8 cm. For both the unoptimized and optimized plans, the dose heterogeneity in the target vessel wall, and length of nontarget vessel receiving 3 Gy, is assessed to compare plans. Optimization results show a 14% dose uniformity within the target is achievable for all vessel lengths. Further, the dose in the adjacent normal tissue is lower in the optimized plans than the unoptimized plans. The work presented in this paper provides a model to address the finite length of RST in IVB treatments. While the results presented are specific to the 90Sr/90Y RST, the methods should apply to other finite length RSTs.

Purpose: To assess the utility of dosimetric/functional metrics as predictors of symptomatic radiation pneumonitis using receiver operating characteristic curves., Methods: Between 1991 and 1999, 277 patients were enrolled on a prospective clinical study to relate radiation therapy (RT) induced changes in lung function with dosimetric and functional metrics. Pre-RT whole and regional functional assessments included pulmonary function tests and single photon emission computed tomography lung perfusion scans. Patients had three-dimensional planning scans and dose calculations (reflecting tissue density heterogeneity) to provide a dose-volume histogram of the lung and associated dosimetric parameters (MLD = mean lung dose, V30 = % of lung receiving >or=30 Gy). Fusion of single photon emission computed tomography and computed tomography scans provides perfusion-weighted dose-function histograms and associated dosimetric parameters (mean perfusion-weighted lung dose). The incidence of clinically relevant radiation pneumonitis requiring steroids was related to the dosimetric and functional metrics. The predictive abilities of models (sensitivity and specificity) were calculated and compared based on the area beneath receiver operating characteristic (ROC) curves (Wilcoxon rank-sum and chi-square)., Results: Twenty-seven of 162 evaluable patients with >or=6 months' follow-up developed pneumonitis requiring steroids. Single metrics were typically not good predictors for pneumonitis ( area under ROC curve = 0.5-0.68). The two-dimensional models (e.g., MLD and pre-RT diffusion capacity for carbon monoxide) generally provided greater ROC areas (0.61-0.72). Overall, the models that considered a measure of pre-RT lung function (i.e., pulmonary function tests), the MLD, and mean perfusion-weighted lung dose were best correlated with outcome (ROC area: 0.7) (p < 0.05 compared to unidimensional models). However, because the area under the ROC curve for these models was <<1, they too seemed not to be ideal., Conclusion: Predicting symptomatic radiation pneumonitis remains difficult. Multiparameter models that consider pre-RT pulmonary function and the three-dimensional dose distribution seem to be best able to predict outcome. Additional studies are needed to better understand the dosimetric/functional determinants of radiation pneumonitis.

Purpose: To assess the efficacy and toxicity of intraresection cavity (131)I-labeled murine antitenascin monoclonal antibody 81C6 and determine its true response rate among patients with newly diagnosed malignant glioma., Patients and Methods: In this phase II trial, 120 mCi of (131)I-labeled murine 81C6 was injected directly into the surgically created resection cavity of 33 patients with previously untreated malignant glioma (glioblastoma multiforme [GBM], n = 27; anaplastic astrocytoma, n = 4; anaplastic oligodendroglioma, n = 2). Patients then received conventional external-beam radiotherapy followed by a year of alkylator-based chemotherapy., Results: Median survival for all patients and those with GBM was 86.7 and 79.4 weeks, respectively. Eleven patients remain alive at a median follow-up of 93 weeks (range, 49 to 220 weeks). Nine patients (27%) developed reversible hematologic toxicity, and histologically confirmed, treatment-related neurologic toxicity occurred in five patients (15%). One patient (3%) required reoperation for radionecrosis., Conclusion: Median survival achieved with (131)I-labeled 81C6 exceeds that of historical controls treated with conventional radiotherapy and chemotherapy, even after accounting for established prognostic factors including age and Karnofsky performance status. The median survival achieved with (131)I-labeled 81C6 compares favorably with either (125)I interstitial brachy-therapy or stereotactic radiosurgery and is associated with a significantly lower rate of reoperation for radionecrosis. Our results confirm the efficacy of (131)I-labeled 81C6 for patients with newly diagnosed malignant glioma and suggest that a randomized phase III study is indicated.

Purpose: To assess the time-dependence of radiation therapy (RT)-induced reductions in regional lung perfusion, as measured by single photon emission computed tomography (SPECT) lung perfusion scans., Methods and Materials: Between 1991 and 1999, 79 patients had SPECT lung perfusion scans before and serially after RT. Changes in regional perfusion were correlated with regional dose using 3D planning tools and image fusion (PLUNC-Plan UNC). Multiple post-RT follow-up scans were evaluated to determine the temporal nature of RT-induced regional perfusion changes. To facilitate the comparison of dose-response curves (DRCs) at different post-RT intervals, each DRC was fit to a linear model and thus described by its slope., Results: There was a dose-dependent reduction in regional perfusion at nearly all time points post-RT (p = 0.0001). The slope of the DRCs for RT-induced reductions in regional perfusion became steeper at essentially each successive follow-up interval (p = 0.0001). However, the increases in slope became progressively smaller at later follow-up intervals. Overall, about 80% of the long-term RT-induced regional perfusion injury was manifest within 12 months post-RT., Conclusion: There is a progression of RT-induced reductions in regional perfusion, with most of this injury manifest within 12 months post-RT. Additional regional injury appears to evolve for years.