Radiation Therapy Oncology Group Trial Research Articles

Regression trees and ensembles for cumulative incidence functions.

The use of cumulative incidence functions for characterizing the risk of one type of event in the presence of others has become increasingly popular over the past two decades. The problems of modeling, estimation and inference have been treated using parametric, nonparametric and semi-parametric methods. Efforts to develop suitable extensions of machine learning methods, such as regression trees and ensemble methods, have begun comparatively recently. In this paper, we propose a novel approach to estimating cumulative incidence curves in a competing risks setting using regression trees and associated ensemble estimators. The proposed methods use augmented estimators of the Brier score risk as the primary basis for building and pruning trees, and lead to methods that are easily implemented using existing R packages. Data from the Radiation Therapy Oncology Group (trial 9410) is used to illustrate these new methods.

Resection following concurrent chemotherapy and high-dose radiation for stage IIIA non–small cell lung cancer

ObjectiveConcern exists regarding surgery after thoracic radiation. We aimed to assess early results of anatomic resection following induction therapy with platinum-based chemotherapy and full-dose thoracic radiation for resectable N2+ stage IIIA non–small cell lung cancer. MethodsTwo prospective trials were recently conducted by NRG Oncology in patients with resectable N2+ stage IIIA non–small cell lung cancer with the primary end point of mediastinal node sterilization following concurrent full-dose chemoradiotherapy (Radiation Therapy Oncology Group trials 0229 and 0839). All surgeons demonstrated postinduction resection expertise. Induction consisted of weekly carboplatin (area under the curve, 2.0) and paclitaxel (50 mg/m2) and concurrent thoracic radiation 60 Gy (0839)/61.2 Gy (0229) in 30 fractions. Patients in study 0839 were randomized 2:1 to weekly panitumumab + chemoradiotherapy or chemoradiotherapy alone during induction. Primary results were similar in all treatment arms and reported previously. Short-term surgical outcomes are reported here. ResultsOne hundred twenty-six patients enrolled; 93 (74%) had anatomic resection, 77 underwent lobectomy, and 16 underwent extended resection. Microscopically margin-negative resections occurred in 85 (91%). Fourteen (15%) resections were attempted minimally invasively, including 2 converted without event. Grade 3 or 4 surgical adverse events were reported in 26 (28%), 30-day mortality in 4 (4%) and 90-day mortality in 5 (5%). Patients undergoing extended resection experienced similar rates of grade 3 or 4 adverse events (odds ratio, 0.95; 95% confidence interval, 0.42-3.8) but higher 30-day (1.3% vs 18.8%) (odds ratio, 17.54; 95% confidence interval, 1.75-181.8) and 90-day mortality (2.6% vs 18.8%) (odds ratio, 8.65; 95% confidence interval, 1.3-56.9). ConclusionsLobectomy was performed safely following full-dose concurrent chemoradiotherapy in these multi-institutional prospective trials; however, increased mortality was noted with extended resections.

AB003. Stereotactic body radiation therapy vs. pulmonary resection

: Pulmonary resection remains the accepted standard of care for early stage non-small cell lung cancer (NSCLC) in patients with adequate cardiopulmonary reserve. Radiation therapy, and in particular stereotactic body radiation therapy (SBRT), has traditionally been recommended as curative therapy for medically unfit patients who harbor early stage lung cancer. As a consequence of the rising success of SBRT in patients with medically inoperable early stage NSCLC (evidenced by Radiation Therapy Oncology Group trials 0236 and 0915), there has been keen interest in exploring this modality in operable patients. SBRT to lung is often very well tolerated, thus making it very attractive to patients. The risk of series complications in carefully selected patients is low. Equipoise among surgeons and the medical community for the use of SBRT as curative therapy for patients eligible for surgery has been limited, thus contributing to the poor accrual and early closure of 3 randomized trials attempting to directly compare SBRT to surgery in operable patients. These trials included the STARS trial (Study of Anastrozole and Radiotherapy Sequencing), the ROSEL trial [Either Surgery or Stereotactic Radiotherapy for Early-Stage (IA) Lung Cancer] and the American College of Surgeons Oncology Group (ACOSOG) Z4099 trial. No preliminary data is available from the ACOSOG trial. The STARS and ROSEL trial randomized operable patients with tumors <4 cm (cT1–T2a) and required invasive mediastinal staging in patients harboring radiographically suspicious lymph nodes. Sublobar resection was not permitted in these trials. Since patient accrual was limited (n=58 total patients) the two trials were combined in a controversial publication that showed improved overall survival and decreased toxicity with SBRT compared to surgery. This has spawned additional randomized trials including the STABLE-MATES trial comparing sublobar resection and SBRT in patients with stage I NSCLC (NCT02468024) with an estimated enrollment of 258 patients, a Veterans Affairs Lung Cancer or Stereotactic Radiotherapy (VALOR) trial (NCT02984761) with estimated enrollment of 670 patients, and lastly, a phase II United Kingdom sponsored SABRTooth study (NCT02629458) that is enrolling up to 54 patients. The lack of randomized data has stimulated multiple publications that retrospectively examine these modalities in single center case series and more recently in larger data sets derived from the National Cancer Database (NCDB), the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database and the United States Veterans Affairs Health Care System. These retrospective analyses are clearly limited by patient selection bias and different levels of staging accuracy. Propensity matched retrospective series showed that overall survival was no different at 1 year but favored surgery at 3 years. Cancer-specific survival (clearly a better outcome measure particularly in elderly patients receiving SBRT) was no different compared to surgery, nor was local failure, or the risk of developing distant metastases. Collectively, the studies that used large data with statistical matching demonstrated a survival advantage of surgery (namely lobectomy) over SBRT for stage I NSCLC but raised awareness of the increased post procedure morbidity and mortality for surgery compared to SBRT. Interestingly, sublobar resection versus SBRT in these large data sets had mixed results with some showing survival improvement with surgery and some showing no survival difference. Surgery appears superior at later time points. In a phase II ablate and resect human clinical trial (MISSILE-NSCLC, NCT02136355) for early stage (T1–T2) NSCLC, 35 patients underwent neoadjuvant SBRT using 54–60 Gy in 3–8 fractions followed by surgery at an interval of 10 weeks. The authors reported a 60% pathologic complete response rate, invoking many questions about local control of SBRT. Assessment of local control after SBRT remains the single most challenging real-world clinical problem. The lung injury post ablation is heterogenous and requires very careful observation with imaging modalities that lack sensitivity and specificity for recurrence. At present, the American Society of Radiation Oncology does not recommend SBRT for operable patients with early stage NSCLC outside of a clinical trial.

Optimizing radiation dose and fractionation for the definitive treatment of locally advanced non-small cell lung cancer.

Radiation therapy is the foundation for treatment of locally advanced non-small cell lung cancer (NSCLC), a disease that is often inoperable and has limited long term survival. Local control of disease is strongly linked to patient survival and continues to be problematic despite continued attempts at changing the dose and fractionation of radiation delivered. Technological advancements such as 4-dimensional computed tomography (CT) based planning, positron emission tomography (PET) based target delineation, and daily image guidance have allowed for ever more accurate and conformal treatments. A limit to dose escalation with conventional fractions of 2 Gy once per day appears to have been reached at 60 Gy in the randomized trial Radiation Therapy Oncology Group (RTOG) 0617. Higher doses were surprisingly associated with worse overall survival. Approaches other than conventional dose escalation have been explored to better control disease including accelerating treatment to limit tumor repopulation both with hyperfractionation and its multiple small (<2 Gy) fractions each day and with hypofractionation and its single larger (>2 Gy) fraction each day. These accelerated regimens are increasingly being used with concurrent chemotherapy, and multiple institutions have reported it as tolerable. Tailoring treatment to individual patient disease and normal anatomic characteristics has been explored with isotoxic dose escalation up to the tolerance of organs at risk, with both hyperfractionation and hypofractionation. Metabolic imaging during and after treatment is increasingly being used to boost doses to residual disease. Boost doses have included moderate hypofractionation of 2-4 Gy, and more recently extreme hypofractionation with stereotactic body radiation therapy (SBRT). In spite of all these changes in dose and fractionation, lung and cardiovascular toxicity remain obstacles that limit disease control and patient survival.

Adaptive parametric prediction of event times in clinical trials.

In event-based clinical trials, it is common to conduct interim analyses at planned landmark event counts. Accurate prediction of the timing of these events can support logistical planning and the efficient allocation of resources. As the trial progresses, one may wish to use the accumulating data to refine predictions. Available methods to predict event times include parametric cure and non-cure models and a nonparametric approach involving Bayesian bootstrap simulation. The parametric methods work well when their underlying assumptions are met, and the nonparametric method gives calibrated but inefficient predictions across a range of true models. In the early stages of a trial, when predictions have high marginal value, it is difficult to infer the form of the underlying model. We seek to develop a method that will adaptively identify the best-fitting model and use it to create robust predictions. At each prediction time, we repeat the following steps: (1) resample the data; (2) identify, from among a set of candidate models, the one with the highest posterior probability; and (3) sample from the predictive posterior of the data under the selected model. A Monte Carlo study demonstrates that the adaptive method produces prediction intervals whose coverage is robust within the family of selected models. The intervals are generally wider than those produced assuming the correct model, but narrower than nonparametric prediction intervals. We demonstrate our method with applications to two completed trials: The International Chronic Granulomatous Disease study and Radiation Therapy Oncology Group trial 0129. Intervals produced under any method can be badly calibrated when the sample size is small and unhelpfully wide when predicting the remote future. Early predictions can be inaccurate if there are changes in enrollment practices or trends in survival. An adaptive event-time prediction method that selects the model given the available data can give improved robustness compared to methods based on less flexible parametric models.

Quality-adjusted survival comparison between androgen deprivation with radiation therapy versus radiation therapy alone for locally advanced prostate cancer: Decision analysis from RTOG 85-31 trial.

265 Background: Radiation Therapy Oncology Group (RTOG) trial 85-31 has shown that addition of androgen deprivation therapy to radiation therapy (RT+ADT) for patients with locally advanced prostate cancer benefits local control and progression-free survival compared to RT alone. However, the survival gain may be diluted with increased toxicity of hormone manipulation. There is a need to develop new decision analysis methods to incorporate survival time and quality of life (QoL) adjusting for various health states and persistent complications. Methods: We previously developed “quality-adjusted survival analysis using duration” (QASAD) and “quality-adjusted survival analysis using probability” (QASAP) to estimate quality-adjusted survival time. The QASAD uses the median duration in each state to weight the utilities, while the QASAP uses the proportional probability of being in each state for weighting. The survival and complication rates of RTOG 85-31 were reconstructed based on published Kaplan-Meier survival curves, and the utility values for states were obtained from the literature. Probabilistic sensitivity analysis was applied using Monte Carlo simulation with 1000 simulated samples. Results: QASAD and QASAP showed that the quality-adjusted life year (QALY) values in RT+ADT were generally higher than those in RT. In probabilistic sensitivity analysis, QASAD resulted in 4.93 (95% bootstrapped confidence interval [CI] = 4.12 to 5.71) for RT and 5.60 (95% CI = 4.30 to 6.48) for RT+ADT. QASAP resulted in 4.85 (95% CI = 4.16 to 5.39) for RT and 4.96 (95% CI = 3.73 to 5.78) for RT+ADT. Conclusions: The decision analyses showed that RT+ADT provided slightly better quality-adjusted survival outcome after treatment than RT alone. The QASAD and QASAP methods may help the decision of optimal treatment balancing between survival gain and unfavorable quality of life. [Table: see text]

Long-Term Outcomes Among Patients Who Achieve Complete or Near-Complete Responses After the Induction Phase of Bladder-Preserving Combined-Modality Therapy for Muscle-Invasive Bladder Cancer: A Pooled Analysis of NRG Oncology/RTOG 9906 and 0233.

To investigate the differences in outcomes among patients with muscle-invasive bladder cancer on NRG Oncology Radiation Therapy Oncology Group protocols 9906 and 0233 who achieved complete response and near-complete response after induction chemoradiation and then completed bladder-preserving therapy with chemoradiation therapy (chemo-RT) to full dose (60-64 Gy). A pooled analysis was performed on 119 eligible patients with muscle-invasive bladder cancer enrolled on NRG Oncology Radiation Therapy Oncology Group trials 9906 and 0233, who were classified as having a complete (T0) or near-complete (Ta or Tis) response after induction chemo-RT and completed consolidation with a total RT dose of at least 60 Gy. Bladder recurrence, salvage cystectomy rates, and disease-specific survival were estimated by the cumulative incidence method and bladder-intact and overall survivals by the Kaplan-Meier method. Among the 119 eligible patients, 101 (85%) achieved T0, and 18 (15%) achieved Ta or Tis after induction chemo-RT and proceeded to consolidation. After a median follow-up of 5.9 years, 36 of 101 T0 patients (36%) versus 5 of 18 Ta or Tis patients (28%) experienced bladder recurrence (P=.52). Thirteen patients among complete responders eventually required late salvage cystectomy for tumor recurrence, compared with 1 patient among near-complete responders (P=.63). Disease-specific, bladder-intact, and overall survivals were not significantly different between T0 and Ta/Tis cases. The bladder recurrence and salvage cystectomy rates of the complete and the near-complete responders were similar. Therefore it is reasonable to recommend that patients with Ta or Tis after induction chemo-RT continue with bladder-sparing therapy with consolidation chemo-RT to full dose (60-64 Gy).

Retrospective Prostate Treatment Plan Comparison for Proton, Tomotherapy, and Cyberknife Therapy

Abstract Background: Twenty-eight cases from patients previously treated for prostate cancer using helical tomotherapy (22 patients) or Cyberknife (6 patients; Accuray, Sunnyvale, California) linear accelerators were selected chronologically between 2009 and 2011 and were replanned using parallel-opposed beam geometry for proton therapy (PT). Methods: Proton data used an IBA (Louvain-La-Neuve, Belgium) beam model that was made available from the Philips Radiation Oncology System (Fitchburg, Wisconsin) as a pre-510(k)–approved Pinnacle treatment planning system. Comparison for the coverage of the planned target volume (expanded clinical target volume) and doses to bladder, rectum, and femoral heads were used to evaluate the plans. Radiation Therapy Oncology Group (RTOG, Philadelphia, Pennsylvania) trial 0815, a prostate intensity-modulated radiation therapy protocol, and trial 0938, a prostate stereotactic radiation therapy protocol, were used as an independent “benchmark” for plan robustness. Results: In ...

A multi-institutional study to assess adherence to lung stereotactic body radiotherapy planning goals.

A multi-institutional planning study was performed to evaluate the frequency that current guidelines established by Radiation Therapy Oncology Group (RTOG) protocols and other literature for lung stereotactic body radiotherapy (SBRT) treatments are followed. A total of 300 patients receiving lung SBRT treatments in four different institutions were retrospectively reviewed. The treatments were delivered using Linac based SBRT (160 patients) or image guided robotic radiosurgery (140). Most tumors were located peripherally (250/300). Median fractional doses and ranges were 18 Gy (8-20 Gy), 12 Gy (6-15 Gy), and 10 Gy (5-12 Gy) for three, four, and five fraction treatments, respectively. The following planning criteria derived from RTOG trials and the literature were used to evaluate the treatment plans: planning target volumes, PTVV 100 ≥ 95% and PTVV 95 ≥ 99%; conformality indices, CI100% < 1.2 and CI50% range of 2.9-5.9 dependent on PTV; total lung-ITV: V20Gy < 10%, V12.5Gy < 15%, and V5Gy < 37%; contralateral lung V5Gy < 26%; and maximum doses for spinal cord, esophagus, trachea/bronchus, and heart and great vessels. Populations were grouped by number of fractions, and dosimetric criteria satisfaction rates (CSRs) were reported. Five fraction regimens were the most common lung SBRT fractionation (46%). The median PTV was 27.2 cm(3) (range: 3.8-419.5 cm(3)). For all plans: mean PTVV 100 was 94.5% (±5.6%, planning CSR: 69.8%), mean PTVV 95 was 98.1% (±4.1%, CSR: 69.5%), mean CI100% was 1.14 (±0.21, CSR: 79.1%, and 16.5% within minor deviation), and mean CI50% was 5.63 (±2.8, CSR: 33.0%, and 28.0% within minor deviation). When comparing plans based on location, peripherally located tumors displayed higher PTVV 100 and PTVV 95 CSR (71.5% and 71.9%, respectively) than centrally located tumors (61.2% and 57.1%, respectively). Overall, the planning criteria were met for all the critical structure such as lung, heart, spinal cord, esophagus, and trachea/bronchus for at least 85% of the patients. Among the various parameters that were used to evaluate the SBRT plans, the CI100% and CI50% were the most challenging criteria to meet. Although the CSRs of organs at risk were higher among all cases, their proximity to the PTV was a significant factor.

Cartographic Mapping and Travel Burden to Assess and Develop Strategies to Improve Minority Access to National Cancer Clinical Trials

To assess how accrual to clinical trials is related to US minority population density relative to clinical trial site location and distance traveled to Radiation Therapy Oncology Group (RTOG) clinical trial sites. Data included member site address and ZIP codes, patient accrual, and patient race or ethnicity and ZIP code. Geographic Information System maps were developed for overall, Latino, and African American accrual to trials by population density. The Kruskal-Wallis test was used to assess differences in distance traveled by site, type of trial, and race or ethnicity. From 2006 to 2009, 6168 patients enrolled on RTOG trials. The RTOG US site distribution is generally concordant with overall population density. Sites with highest accrual are located throughout the United States and parts of Canada and do not cluster, nor does highest minority accrual cluster in areas of highest US minority population density. Of the 4913 US patients with complete data, patients traveled a median of 11.6 miles to participate in clinical trials. Whites traveled statistically longer distances (12.9 miles; P<.0001) to participate, followed by Latinos (8.22 miles) and African Americans (5.85 miles). Patients were willing to drive longer distances to academic sites than community sites, and there was a trend toward significantly longer median travel for therapeutic versus cancer control or metastatic trials. Location matters, but only to a degree, for minority compared with nonminority participation in clinical trials. Geographic Information System tools help identify gaps in geographic access and travel burden for clinical trials participation. Strategies that emerged using these tools are discussed.

Variation over time and interdependence between disease progression and death among patients with glioblastoma on RTOG 0525.

We assessed the longitudinal hazard characteristics for death and progression in patients with glioblastoma, evaluated the impact of prognostic factors and treatment on the hazard within different time intervals to determine if effects are time varying, and quantified the influence of progression on survival. Among patients randomized to Radiation Therapy Oncology Group trial 0525, which compared dose-dense with standard-dose temozolomide, we estimated the hazards of death and treatment failure (death or progression) over time and their interdependence. The peak hazard of death was reached at around 16 months with a slow decline after that; the hazard of progression/death reached a peak at around 6 months and decreased dramatically thereafter. The survival advantages for patients with MGMT gene promoter methylation and recursive partitioning analysis class III were substantial in the first 2 years, but lessened thereafter. The progression-free survival benefit of dose-dense over standard-dose temozolomide occurred in the first 6 months (hazard ratio: 0.70; 95% CI: 0.58-0.86; P < .001), although it diminished thereafter. After adjusting for recursive partitioning analysis class and MGMT methylation status, the hazard ratio of death for patients who had progressed over nonprogressors was 6.59 (95% CI: 5.15-8.43; P < .001). After the peak hazard of death, a consistently high hazard remains, but it is lower than in the peak period. The progression hazard peak is earlier, and then hazard consistently declines. The rate of dying after disease progression is about 6.59 times the rate for nonprogressors, suggesting that progression-free survival may be a relevant clinical endpoint.

Human papillomavirus and overall survival after progression of oropharyngeal squamous cell carcinoma.

Risk of cancer progression is reduced for patients with human papillomavirus (HPV) -positive oropharynx cancer (OPC) relative to HPV-negative OPC, but it is unknown whether risk of death after progression is similarly reduced. Patients with stage III-IV OPC enrolled onto Radiation Therapy Oncology Group trials 0129 or RTOG 0522 who had known tumor p16 status plus local, regional, and/or distant progression after receiving platinum-based chemoradiotherapy were eligible for a retrospective analysis of the association between tumor p16 status and overall survival (OS) after disease progression. Rates were estimated by Kaplan-Meier method and compared by log-rank; hazard ratios (HRs) were estimated by Cox models. Tests and models were stratified by treatment protocol. A total of 181 patients with p16-positive (n = 105) or p16-negative (n = 76) OPC were included in the analysis. Patterns of failure and median time to progression (8.2 v 7.3 months; P = .67) were similar for patients with p16-positive and p16-negative tumors. After a median follow-up period of 4.0 years after disease progression, patients with p16-positive OPC had significantly improved survival rates compared with p16-negative patients (2-year OS, 54.6% v 27.6%; median, 2.6 v 0.8 years; P < .001). p16-positive tumor status (HR, 0.48; 95% CI, 0.31 to 0.74) and receipt of salvage surgery (HR, 0.48; 95% CI; 0.27 to 0.84) reduced risk of death after disease progression whereas distant versus locoregional progression (HR, 1.99; 95% CI, 1.28 to 3.09) increased risk, after adjustment for tumor stage and cigarette pack-years at enrollment. Tumor HPV status is a strong and independent predictor of OS after disease progression and should be a stratification factor for clinical trials for patients with recurrent or metastatic OPC.

Factor analysis of the modified Sexual Adjustment Questionnaire-Male.

The Sexual Adjustment Questionnaire (SAQ) is used in National Cancer Institute-sponsored clinical trials as an outcome measure for sexual functioning. The tool was revised to meet the needs for a clinically useful, theory-based outcome measure for use in both research and clinical settings. This report describes the modifications and validity testing of the modified Sexual Adjustment Questionnaire-Male (mSAQ-Male). This secondary analysis of data from a large Radiation Therapy Oncology Group trial employed principal axis factor analytic techniques in estimating validity of the revised tool. The sample size was 686; most subjects were White, older than the age 60 years, and with a high school education and a Karnofsky performance scale (KPS) score of greater than 90. A 16-item, 3-factor solution resulted from the factor analysis. The mSAQ-Male was also found to be sensitive to changes in physical sexual functioning as measured by the KPS. The mSAQ-Male is a valid self-report measure of sexuality that can be used clinically to detect changes in male sexual functioning.

Net Clinical Benefit Analysis of Radiation Therapy Oncology Group 0525: A Phase III Trial Comparing Conventional Adjuvant Temozolomide With Dose-Intensive Temozolomide in Patients With Newly Diagnosed Glioblastoma

Radiation Therapy Oncology Group trial 0525 tested whether dose-intensifying temozolomide versus standard chemoradiotherapy improves overall survival (OS) or progression-free survival (PFS) in newly diagnosed glioblastoma. Tests of neurocognitive function (NCF) and symptoms (using the MD Anderson Symptom Inventory-Brain Tumor module; MDASI-BT) and of quality of life (European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ] -C30/BN20) examined the net clinical benefit (NCB) of therapy. NCF tests (Hopkins Verbal Learning Test-Revised, Trail Making Test, and Controlled Oral Word Association), MDASI-BT, and EORTC QLQ-C30/BN20 were completed in a subset of patients. Multivariate Cox proportional hazard regression modeling determined the prognostic value of baseline and early change from baseline to cycle 1 for OS and PFS. Two-sample proportional test statistic was used to evaluate differences between treatments (dose-dense v standard-dose) on NCB measures from baseline to cycle 4 in stable patients. Overall, 182 patients participated in the study. Baseline NCF tests and the physical functioning quality of life scale were associated with OS and PFS. Baseline to cycle 1 in all NCB components were associated with OS and PFS. There was greater deterioration in the dose-dense arm from baseline to cycle 4 in the Global Health and Motor Function subscales (EORTC QLQ-C30/BN20) as well as in overall symptom burden, overall symptom interference, and activity-related symptom interference subscales (MDASI-BT). There were no between-arm differences in NCF. Longitudinal collection of NCB measures is feasible in cooperative group studies and provides an added dimension to standard outcome measures. Greater adverse symptom burden and functional interference, as well as decreased global health and motor function were observed in patients randomly assigned to the dose-dense arm. Baseline and early change in NCB measures were associated with decreased rates of survival.

Upper abdominal normal organ contouring guidelines and atlas: A Radiation Therapy Oncology Group consensus

PurposeTo standardize upper abdominal normal organ contouring guidelines for Radiation Therapy Oncology Group (RTOG) trials. Methods and MaterialsTwelve expert radiation oncologists contoured the liver, esophagus, gastroesophageal junction (GEJ), stomach, duodenum, and common bile duct (CBD), and reviewed and edited 33 additional normal organ and blood vessel contours on an anonymized patient computed tomography (CT) dataset. Contours were overlaid and compared for agreement using MATLAB (MathWorks, Natick, MA). S95 contours, defined as the binomial distribution to generate 95% group consensus contours, and normal organ contouring definitions were generated and reviewed by the panel. ResultsThere was excellent consistency and agreement of the liver, duodenal, and stomach contours, with substantial consistency for the esophagus contour, and moderate consistency for the GEJ and CBD contours using a Kappa statistic. Consensus definitions, detailed normal organ contouring recommendations and high-resolution images were developed. ConclusionsConsensus contouring guidelines and a CT image atlas should improve contouring uniformity in radiation oncology clinical planning and RTOG trials.

Five-year outcome of concurrent radiotherapy and chemotherapy in Saudi women with locally advanced cervical cancer: single-institution experience

BACKGROUND AND OBJECTIVESWe aimed to evaluate long-term treatment outcomes and toxicity profile of combined radiotherapy and chemotherapy in Saudi women with locally advanced cervical cancer.DESIGN AND SETTINGSRetrospective study in a tertiary care cancer center in Riyadh, Saudi Arabia.METHODS AND MATERIALSThe medical records of patients with histopathologically proven, locally advanced cervical cancer were analyzed. These patients received three-dimensional conformal radiotherapy with concurrent chemotherapy followed by high dose rate brachytherapy in our center between July 2007 and April 2012. The data regarding the safety profile, response rates, occurrence of locoregional or distant failure, disease-free survival, and overall survival rates were recorded.RESULTSThe median follow-up period was 60 months (range, 8–66) for 74 patients. The median age of study population was 52.3 years (32–78), and the stage IIB was the predominant stage (49 patients [66.2%]). A total of 45 patients (60.9%) had radiologic-positive pelvic ± para-aortic lymphadenopathy. The 5-year locoregional and distant control rates were 84.3% and 78.5%, respectively. The 5-year disease-free and overall survival rates were 75.7% and 64.5%, respectively. Stage, nodal status, and hemoglobin levels were found to be important prognostic factors for locoregional and distant control. Acute grade 3 hematological and nonhematological toxicities were seen in 4 (5.4%) and 4 (5.4%) patients. Late toxicities were mild, and only 1 (1.4%) patient presented with subacute intestinal obstruction.CONCLUSIONConcurrent chemoradiation in Saudi women with locally advanced cervical cancer showed better locoregional and distant control and survival rates with minimal toxicity.

Bladder Preservation Therapy for Muscle-Invading Bladder Cancers on Radiation Therapy Oncology Group Trials 8802, 8903, 9506, and 9706: Vascular Endothelial Growth Factor B Overexpression Predicts for Increased Distant Metastasis and Shorter Survival

From 1988 to 1999, the Radiation Therapy Oncology Group (RTOG) conducted four prospective studies (8802, 8903, 9506, 9706) of patients with clinical stage T2-4a muscle-invasive bladder cancer. Treatment was selective bladder preservation using transurethral surgery (TURBT) plus cisplatin-based induction and consolidation chemoradiation regimens, reserving radical cystectomy for invasive tumor recurrence. We investigated vascular endothelial growth factor (VEGF) pathway biomarkers in this unique clinical dataset (median follow-up of 3.1 years). A total of 43 patients with tissue available from the entry TURBT were included in this analysis. Expression of VEGF ligands and receptors were quantified and scored by the AQUA platform (HistoRX, now Genoptix, Carlsbad, CA) and analyzed after median split. VEGF expression levels were not associated with increased rates of complete response to induction chemoradiation. Higher levels of cytoplasmic VEGF-B, VEGF-C, and VEGF-R2 were associated with decreased overall survival rates. The 3-year overall survival estimates for high and low expressers were 43.7% and 75% for VEGF-B cytoplasm (p = .01), 40.2% and 86.7% for VEGF-C cytoplasm (p = .01), and 49.7% and 66.7% for VEGF-R2 cytoplasm (p = .02). Higher expression levels of cytoplasm VEGF-B were associated with higher rates of distant failure (p = .01). Although VEGF ligands and receptors do not appear to be associated with complete response to induction chemoradiation for muscle-invasive bladder cancer, we report significant associations with overall survival and distant failure for certain VEGF family members.

Pancreatic cancer – cost for overtreatment with gemcitabine

Gemcitabine has been the standard chemotherapeutic agent in pancreatic cancer. However, two-thirds of pancreatic tumors display low expression of human equilibrative nucleoside transporter 1 (hENT1), which mediates cellular entry of the drug, and do not respond to gemcitabine therapy. The objective was to determine the costs of gemcitabine overtreatment and the cost-effectiveness of hENT1 testing using a Swedish pancreatic cancer cohort. Material and methods. The study population included 87 patients that were diagnosed with pancreatic cancer during 2008–2010 at Skåne University Hospital, Lund. A detailed review of treatments, side effects and resource utilization was performed. The proportion of hENT1-low was estimated at two-thirds based on previous evaluations of tumor samples from the Radiation Therapy Oncology Group (RTOG) trial 9704, the German AIO Pancreatic Cancer Group (AIO-PK) trial 0104, the Low hENT1 and Adenocarcinoma of the Pancreas (LEAP) trial and the authors’ own institution. The cost of the hENT1 test was estimated at €50–200. Results. Sixty patients received gemcitabine and the other 27 best supportive care. Drug administration and hospitalization were the main expenditures. Grade 3 and 4 toxicities occurred in 42%, the most common being neutropenia (18%). The hospital costs related to gemcitabine overtreatment amounted to €5358 per pancreatic cancer patient, corresponding to as much as one-third of the total treatment cost. The health economical costs amounted to €9449 per patient when including indirect costs. Using hENT1 testing to select patients for gemcitabine therapy would save €8.6 million in Sweden each year. Conclusion. Total costs related to gemcitabine overtreatment were high. Individualizing gemcitabine treatment is cost-saving and would reduce unnecessary treatment-related toxicity.

On the Merits and Limitations of Whole-Brain Radiation Therapy

Brain metastases are a common event in the progression of many human malignancies. In the article that accompanies this editorial, Soffietti et al present data reporting health-related quality of life (HRQOL)outcomesinpatientsenrolledontoEuropeanOrganisationfor Research and Treatment of Cancer (EORTC) trial 22952-26001. This is the first such analysis in a randomized trial of observation or whole-brain radiation therapy (WBRT) after focal therapy (surgery or stereotactic radiosurgery [SRS]). The primary end point results were reported by Kocher et al in 2011 and eloquently editorialized by Mehta in the same issue of Journal of Clinical Oncology. Few topics in oncology have stirred more controversy and partisanship than the appropriate use and role of WBRT in the modern practice of oncology. Deeply held biases have sometimes been defended with a fervor that cannot be easily justified by the scant available evidence. Nonetheless, recent developments have shed some light on the potential merits and limitations of WBRT. All patients with brain metastases typically receive corticosteroids, which will improve edema and neurologic deficits in approximately 70% of patients. Nonetheless, the median survival with corticosteroids alone is approximately 2 months. WBRT has been the mainstay of therapy for patients with intracranial metastases and is associated with increases in the median survival of these patients to approximately 4 to 6 months. In a pooled recursive partitioning analysis of patients treated with WBRT on Radiation Therapy Oncology Group (RTOG) trials, the median survivals were 7, 4, and 2 months, respectively, for patients in the most favorable, intermediate, and poor prognostic subgroups. A cumulative response rate of approximately 60% can be anticipated with WBRT. The debate over the clinical benefit of WBRT versus the potential risks of treatment have led to interest in identifying a group of patients with limited cranial metastases who can be treated adequately with focal therapies alone (surgery or SRS), withholding WBRT until progression (Table 1). Three randomized trials have examined the incremental benefit of adding WBRT to focal therapy alone in patients with limited cranial metastases. Patchell et al reported improved local control (90% v 54%), elsewhere control (86% v 63%), and cumulative intracranial control (82% v 30%) with WBRT compared with observation after surgical resection of a single brain metastasis. There was no improvement in overall survival, but patients in the WBRT arm were less likely to suffer neurologic death. This study is often misinterpreted as a negative study because of the lack of improvement in survival. However, this trial was designed and powered for intracranial disease control; survival was a secondary end point. From the standpoint of intracranial disease control, this was indeed a positive trial, and the findings are congruent with data from the Japanese Radiation Oncology Study Group (JROSG) 99-1 trial. Aoyama et al reported results for 132 patients with one to four brain metastases, each less than 3 cm, who were randomly assigned to SRS alone or WBRT and SRS. The WBRT arm had superior local control, distant brain control, and total intracranial control. Forty-three percent of patients on the SRS-alone arm required salvage therapy, compared with 15% when WBRT was added. Interestingly, this trial demonstrated improvements in local control of the index lesions with WBRT, presumably because of the higher doses received when WBRT was delivered. This finding seems to undermine the rationale for SRS alone (at least on the

Integrated phase II/III clinical trials in oncology: A case study

Integrated phase II/III trial designs implement the phase II and phase III aspects of oncology studies into a single trial. Despite a body of literature discussing the merits of integrated phase II/III clinical trial designs within the past two decades, implementation of this design has been limited in oncology studies. We provide a brief discussion of the potential advantages and disadvantages of integrated phase II/III clinical trial designs in oncology and provide an example of the operating characteristics of a Radiation Therapy Oncology Group (RTOG) trial. We review the differences among proposed integrated phase II/III designs. Then, we illustrate the use of the design in a brain tumor trial to be conducted by the RTOG and examine the impact of association between endpoints on design performance in terms of type I error, power, study duration, and expected sample size. Although integrated phase II/III designs should not be used in all situations, under appropriate conditions, significant gains can be achieved when using integrated phase II/III designs, including smaller sample size, time and resources savings, and shorter study duration. Data submission without delay and sufficient evaluation of intermediate endpoints are assumed. Although there are potential benefits in using phase II/III designs, there also may be disadvantages. We recommend running design simulations incorporating theoretical and practical issues before implementing an integrated phase II/III design.