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Bonner J.A.,University of Alabama at Birmingham | Harari P.M.,University of Wisconsin - Madison | Giralt J.,University of Barcelona | Cohen R.B.,Fox Chase Cancer Center | And 9 more authors.
The Lancet Oncology | Year: 2010

Background: Previous results from our phase 3 randomised trial showed that adding cetuximab to primary radiotherapy increased overall survival in patients with locoregionally advanced squamous-cell carcinoma of the head and neck (LASCCHN) at 3 years. Here we report the 5-year survival data, and investigate the relation between cetuximab-induced rash and survival. Methods: Patients with LASCCHN of the oropharynx, hypopharynx, or larynx with measurable disease were randomly allocated in a 1:1 ratio to receive either comprehensive head and neck radiotherapy alone for 6-7 weeks or radiotherapy plus weekly doses of cetuximab: 400 mg/m2 initial dose, followed by seven weekly doses at 250 mg/m2. Randomisation was done with an adaptive minimisation technique to balance assignments across stratification factors of Karnofsky performance score, T stage, N stage, and radiation fractionation. The trial was un-blinded. The primary endpoint was locoregional control, with a secondary endpoint of survival. Following discussions with the US Food and Drug Administration, the dataset was locked, except for queries to the sites about overall survival, before our previous report in 2006, so that an independent review could be done. Analyses were done on an intention-to-treat basis. Following completion of treatment, patients underwent physical examination and radiographic imaging every 4 months for 2 years, and then every 6 months thereafter. The trial is registered at www.ClinicalTrials.gov, number NCT00004227. Findings: Patients were randomly assigned to receive radiotherapy with (n=211) or without (n=213) cetuximab, and all patients were followed for survival. Updated median overall survival for patients treated with cetuximab and radiotherapy was 49·0 months (95% CI 32·8-69·5) versus 29·3 months (20·6-41·4) in the radiotherapy-alone group (hazard ratio [HR] 0·73, 95% CI 0·56-0·95; p=0·018). 5-year overall survival was 45·6% in the cetuximab-plus-radiotherapy group and 36·4% in the radiotherapy-alone group. Additionally, for the patients treated with cetuximab, overall survival was significantly improved in those who experienced an acneiform rash of at least grade 2 severity compared with patients with no rash or grade 1 rash (HR 0·49, 0·34-0·72; p=0·002). Interpretation: For patients with LASCCHN, cetuximab plus radiotherapy significantly improves overall survival at 5 years compared with radiotherapy alone, confirming cetuximab plus radiotherapy as an important treatment option in this group of patients. Cetuximab-treated patients with prominent cetuximab-induced rash (grade 2 or above) have better survival than patients with no or grade 1 rash. Funding: ImClone Systems, Merck KGaA, and Bristol-Myers Squibb. © 2010 Elsevier Ltd. All rights reserved. Source

Trotti III A.,University of South Florida | Zhang Q.,Statistical Center | Bentzen S.M.,University of Wisconsin - Madison | Emami B.,Loyola University | And 7 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2014

Purpose To compare hyperfractionation versus standard fractionation for T2N0 vocal cord carcinoma in a randomized controlled trial. Methods and Materials Patients with T2 vocal cord cancer were stratified by substage (T2a vs T2b) and randomly assigned to receive either hyperfractionation (HFX) to 79.2 Gy in 66 fractions of 1.2 Gy given twice a day, or standard fractionation (SFX) to 70 Gy in 35 fractions given once a day. The trial was designed to detect a 55% reduction in the local failure hazard rate with 80% statistical power. Results Between April 1996 and July 2003, a total of 250 patients were enrolled. Of 239 patients analyzable for outcomes, 94% were male, 83% had a Karnofsky performance status of 90-100, and 62% had T2a tumor. Median follow-up for all surviving patients was 7.9 years (range, 0.6-13.1 years). The 5-year local control (LC) rate was 8 points higher but not statistically significant (P=.14 for HFX [78%] vs SFX [70%]), corresponding to a 30% hazard rate reduction. The 5-year disease-free survival (DFS) was 49% versus 40% (P=.13) and overall survival (OS) was 72% versus 63% (P=.29). HFX was associated with higher rates of acute skin, mucosal, and laryngeal toxicity. Grade 3-4 late effects were similar with a 5-year cumulative incidence of 8.5% (3.4%-13.6%) after SFX and 8.5% (3.4%-13.5%) after HFX. Conclusions The 5-year local control was modestly higher with HFX compared to SFX for T2 glottic carcinoma, but the difference was not statistically significant. These results are consistent with prior studies of hyperfractionation showing a benefit in local control. Substaging by T2a versus T2b carries prognostic value for DFS and OS. For cost and convenience reasons other altered fractionation schedules have been adopted in routine practice. © 2014 Elsevier Inc. All rights reserved. Source

Verhoven B.,University of Wisconsin - Madison | Yan Y.,Statistical Center | Ritter M.,University of Wisconsin - Madison | Khor L.-Y.,Case Medical Center | And 6 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2013

Purpose: The association of Ki-67 staining index (Ki67-SI) with overall survival (OS), disease-specific mortality (DSM), distant metastasis (DM), and biochemical failure (BF) was examined in men with favorable- to intermediate-risk prostate cancer receiving radiation therapy (RT) alone or with short-term androgen deprivation (ADT) in Radiation Therapy Oncology Group (RTOG) 94-08. Methods and Materials: 468 patients (23.6%) on RTOG 94-08 had sufficient tissue for Ki67-SI analysis. The median follow-up time was 7.9 years. Ki67-SI was determined by immunohistochemistry and quantified manually and by image analysis. Correlative analysis versus clinical outcome was performed using the third quartile (≥Q3) cutpoint. A proportional hazards multivariable analysis (MVA) dichotomized covariates in accordance with trial stratification and randomization criteria. Results: In MVAs adjusted for all treatment covariates, high Ki67-SI (≥Q3) was correlated with increased DSM (hazard ratio [HR] 2.48, P=.03), DM (HR 3.5, P=.002), and BF (HR 3.55, P<.0001). MVA revealed similar Ki67-associated hazard ratios in each separate treatment arm for DSM, DM, and BF; these reached significance only for DM in the RT-alone arm and for BF in both arms. Ki67-SI was not a significant predictor of intraprostatic recurrence assessed by repeated biopsy 2 years after treatment. Patients with a high or low Ki67-SI seemed to experience a similar relative benefit from the addition of ADT to radiation. Conclusions: High Ki67-SI independently predicts for increased DSM, DM, and protocol BF in primarily intermediate-risk prostate cancer patients treated with RT with or without ADT on RTOG 94-08 but does not predict for local recurrence or for increased relative benefit from ADT. This and prior studies lend support for the use of Ki67-SI as a stratification factor in future trials. © 2013 Elsevier Inc. All rights reserved. Source

Seidenwurm D.,Radiological Associates of Sacramento | Rosenberg R.,University of New Mexico
Journal of the American College of Radiology | Year: 2010

The US Preventive Services Task Force recently promulgated revised guidelines for screening mammography. Criticisms were related to the undervaluation of future lives saved and the overvaluation of negative impacts of mammography. Radiologists downplayed quality-of-life factors, potentially understating the value of all imaging procedures. The task force's recommendations for core needle biopsy, based on similar conceptual frameworks, were not met with equivalent responses. Full appreciation of the costs and benefits of screening provides the basis for making the best decisions for individuals and populations. This is undermined by the mixed messages that patients and physicians receive during clinical encounters and through other means. Quantitative approaches to medical care are valid on their own terms and when evaluated in the individual context. Insights from behavioral economics and political science inform discussion of population-based medical interventions. Preventing harm from medical interventions satisfies both the "primum non nocere" dictum and the loss aversion heuristic concordantly. The most effective medical care is provided when benefits are maximized and complications are minimized, especially when the harms occur immediately and the benefits are delayed. The importance of both quality of life and longevity in health care decision making require minimizing negative impacts of mammography when screening low-risk populations. Current practice differs significantly from the successful randomized trials, front-loading costs of false-positive examinations, and overtreatment. By decreasing false-positive mammographic results through adherence to ACR BI-RADS® recommendations, radiologists can answer critics of early and frequent screening while still reducing cancer deaths. © 2010 American College of Radiology. Source

Curran Jr. W.J.,Emory University | Paulus R.,Radiation Therapy Oncology Group Statistical Center | Langer C.J.,University of Pennsylvania | Komaki R.,University of Houston | And 11 more authors.
Journal of the National Cancer Institute | Year: 2011

Background The combination of chemotherapy with thoracic radiotherapy (TRT) compared with TRT alone has been shown to confer a survival advantage for good performance status patients with stage III non-small cell lung cancer. However, it is not known whether sequential or concurrent delivery of these therapies is the optimal combination strategy. Methods A total of 610 patients were randomly assigned to two concurrent regimens and one sequential chemotherapy and TRT regimen in a three-arm phase III trial. The sequential arm included cisplatin at 100 mg/m2 on days 1 and 29 and vinblastine at 5 mg/m2 per week for 5 weeks with 60 Gy TRT beginning on day 50. Arm 2 used the same chemotherapy regimen as arm 1 with 60 Gy TRT once daily beginning on day 1. Arm 3 used cisplatin at 50 mg/m2 on days 1, 8, 29, and 36 with oral etoposide at 50 mg twice daily for 10 weeks on days 1, 2, 5, and 6 with 69.6 Gy delivered as 1.2 Gy twice-daily fractions beginning on day 1. The primary endpoint was overall survival, and secondary endpoints included tumor response and time to tumor progression. Kaplan-Meier analyses were used to assess survival, and toxic effects were examined using the Wilcoxon rank sum test. All statistical tests were two-sided.ResultsMedian survival times were 14.6, 17.0, and 15.6 months for arms 1-3, respectively. Five-year survival was statistically significantly higher for patients treated with the concurrent regimen with once-daily TRT compared with the sequential treatment (5-year survival: sequential, arm 1, 10% [20 patients], 95% confidence interval [CI] = 7% to 15%; concurrent, arm 2, 16% [31 patients], 95% CI = 11% to 22%, P =. 046; concurrent, arm 3, 13% [22 patients], 95% CI = 9% to 18%). With a median follow-up time of 11 years, the rates of acute grade 3-5 nonhematologic toxic effects were higher with concurrent than sequential therapy, but late toxic effects were similar.ConclusionConcurrent delivery of cisplatin-based chemotherapy with TRT confers a long-term survival benefit compared with the sequential delivery of these therapies. © 2011 The Author. Source

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