Daniels T.B.,Mayo Medical School |
Brown P.D.,Mayo Medical School |
Felten S.J.,Cancer Center Statistics |
Wu W.,Cancer Center Statistics |
And 6 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2011
Purpose: A prognostic index for survival was constructed and validated from patient data from two European Organisation for Research and Treatment of Cancer (EORTC) radiation trials for low-grade glioma (LGG). We sought to independently validate this prognostic index with a separate prospectively collected data set (Intergroup 86-72-51). Methods and Materials: Two hundred three patients were treated in a North Central Cancer Treatment Group-led trial that randomized patients with supratentorial LGG to 50.4 or 64.8 Gy. Risk factors from the EORTC prognostic index were analyzed for prognostic value: histology, tumor size, neurologic deficit, age, and tumor crossing the midline. The high-risk group was defined as patients with more than two risk factors. In addition, the Mini Mental Status Examination (MMSE) score, extent of surgical resection, and 1p19q status were also analyzed for prognostic value. Results: On univariate analysis, the following were statistically significant (p < 0.05) detrimental factors for both progression-free survival (PFS) and overall survival (OS): astrocytoma histology, tumor size, and less than total resection. A Mini Mental Status Examination score of more than 26 was a favorable prognostic factor. Multivariate analysis showed that tumor size and MMSE score were significant predictors of OS whereas tumor size, astrocytoma histology, and MMSE score were significant predictors of PFS. Analyzing by the EORTC risk groups, we found that the low-risk group had significantly better median OS (10.8 years vs. 3.9 years, p < 0.0001) and PFS (6.2 years vs. 1.9 years, p < 0.0001) than the high-risk group. The 1p19q status was available in 66 patients. Co-deletion of 1p19q was a favorable prognostic factor for OS vs. one or no deletion (median OS, 12.6 years vs. 7.2 years; p = 0.03). Conclusions: Although the low-risk group as defined by EORTC criteria had a superior PFS and OS to the high-risk group, this is primarily because of the influence of histology and tumor size. Co-deletion of 1p19q is a prognostic factor. Future studies are needed to develop a more refined prognostic system that combines clinical prognostic features with more robust molecular and genetic data. Copyright © 2011 Elsevier Inc.
Buyse M.,International Drug Development Institute |
Sargent D.J.,Cancer Center Statistics |
Grothey A.,Rochester College |
Matheson A.,Fondation ARCAD |
De Gramont A.,Hopital Saint Antoine
Nature Reviews Clinical Oncology | Year: 2010
Biomarkers and surrogate end points have great potential for use in clinical oncology, but their statistical validation presents major challenges, and few biomarkers have been robustly confirmed. Provisional supportive data for prognostic biomarkers, which predict the likely outcome independently of treatment, is possible through small retrospective studies, but it has proved more difficult to achieve robust multi-site validation. Predictive biomarkers, which predict the likely response of patients to specific treatments, require more extensive data for validation, specifically large randomized clinical trials and meta-analysis. Surrogate end points are even more challenging to validate, and require data demonstrating both that the surrogate is prognostic for the true end point independently of treatment, and that the effect of treatment on the surrogate reliably predicts its effect on the true end point. In this Review, we discuss the nature of prognostic and predictive biomarkers and surrogate end points, and examine the statistical techniques and designs required for their validation. In cases where the statistical requirements for validation cannot be rigorously achieved, the biological plausibility of an end point or surrogate might support its adoption. No consensus yet exists on processes or standards for pragmatic evaluation and adoption of biomarkers and surrogate end points in the absence of robust statistical validation. © 2010 Macmillan Publishers Limited. All rights reserved.
Renfro L.A.,Cancer Center Statistics |
Shi Q.,Cancer Center Statistics |
Sargent D.J.,Mayo Medical School |
Carlin B.P.,University of Minnesota
Statistics in Medicine | Year: 2012
A two-stage model for evaluating both trial-level and patient-level surrogacy of correlated time-to-event endpoints has been introduced, using patient-level data when multiple clinical trials are available. However, the associated maximum likelihood approach often suffers from numerical problems when different baseline hazards among trials and imperfect estimation of treatment effects are assumed. To address this issue, we propose performing the second-stage, trial-level evaluation of potential surrogates within a Bayesian framework, where we may naturally borrow information across trials while maintaining these realistic assumptions. Posterior distributions on surrogacy measures of interest may then be used to compare measures or make decisions regarding the candidacy of a specific endpoint. We perform a simulation study to investigate differences in estimation performance between traditional maximum likelihood and new Bayesian representations of common meta-analytic surrogacy measures, while assessing sensitivity to data characteristics such as number of trials, trial size, and amount of censoring. Furthermore, we present both frequentist and Bayesian trial-level surrogacy evaluations of time to recurrence for overall survival in two meta-analyses of adjuvant therapy trials in colon cancer. With these results, we recommend Bayesian evaluation as an attractive and numerically stable alternative in the multitrial assessment of potential surrogate endpoints. © 2011 John Wiley & Sons, Ltd.
Heemers H.V.,Roswell Park Cancer Institute |
Schmidt L.J.,Mayo Medical School |
Sun Z.,Mayo Medical School |
Regan K.M.,Mayo Medical School |
And 6 more authors.
Cancer Research | Year: 2011
The androgen receptor (AR) is the principal target for treatment of non-organ-confined prostate cancer (PCa). Androgen deprivation therapies (ADT) directed against the AR ligand-binding domain do not fully inhibit androgen-dependent signaling critical for PCa progression. Thus, information that could direct the development of more effective ADTs is desired. Systems and bioinformatics approaches suggest that considerable variation exists in the mechanisms by which AR regulates expression of effector genes, pointing to a role for secondary transcription factors. A combination of microarray and in silico analyses led us to identify a 158-gene signature that relies on AR along with the transcription factor SRF (serum response factor), representing less than 6% of androgen-dependent genes. This AR-SRF signature is sufficient to distinguish microdissected benign and malignant prostate samples, and it correlates with the presence of aggressive disease and poor outcome. The ARSRF signature described here associates more strongly with biochemical failure than other AR target gene signatures of similar size. Furthermore, it is enriched in malignant versus benign prostate tissues, compared with other signatures. To our knowledge, this profile represents the first demonstration of a distinct mechanism of androgen action with clinical relevance in PCa, offering a possible rationale to develop novel and more effective forms of ADT. ©2011 AACR.
Gonsalves W.I.,Mayo Medical School |
Mahoney M.R.,Mayo Medical School |
Sargent D.J.,Cancer Center Statistics |
Nelson G.D.,Mayo Medical School |
And 11 more authors.
Journal of the National Cancer Institute | Year: 2014
Background KRAS and BRAF V600E mutations are important predictive and prognostic markers, respectively, in colon cancer, but little is known about patient and clinical factors associated with them. Methods Two thousand three hundred twenty-six of 3397 patients in the N0147 phase III adjuvant trial for stage III colon cancer completed a patient questionnaire. Primary tumors were assessed for KRAS and BRAF V600E mutations and defective mismatch repair (dMMR) status. Logistic regression models and categorical data analysis were used to identify associations of patient and tumor characteristics with mutation status. All statistical tests were two-sided. Results KRAS (35%) and BRAF V600E (14%) mutations were nearly mutually exclusive. KRAS mutations were more likely to be present in patients without a family history of colon cancer and never smokers. Tumors with KRAS mutations were less likely to have dMMR (odds ratio [OR] = 0.21; 95% confidence interval [CI] = 0.15 to 0.31; P <. 001) and high-grade histology (OR = 0.73; 95% CI = 0.59 to 0.92; P <. 001) but were more often right-sided. Among KRAS-mutated tumors, those with a Gly13Asp mutation tended to have dMMR and high-grade histology. Tumors with BRAF V600E mutations were more likely to be seen in patients who were aged 70 years or older (OR = 3.33; 95% CI = 2.50 to 4.42; P <. 001) and current or former smokers (OR = 1.64; 95% CI = 1.26 to 2.14; P <. 001) but less likely in non-whites and men. Tumors with BRAF V600E mutations were more likely to be right-sided and to have four or more positive lymph nodes, high-grade histology, and dMMR. Conclusions Specific patient and tumor characteristics are associated with KRAS and BRAF V600E mutations. © 2014 The Author 2014. Published by Oxford University Press. All rights reserved.
Mansfield A.S.,Mayo Medical School |
Holtan S.G.,Mayo Medical School |
Grotz T.E.,Mayo Medical School |
Allred J.B.,Cancer Center Statistics |
And 3 more authors.
Modern Pathology | Year: 2011
In order to characterize the degree of immunosuppression in regional immunity in patients with melanoma, we used immunohistochemistry to analyze markers of T-cell subtype and polarity, costimulation, dendritic cell maturation, monocytes, lymphatic vasculature, and angiogenesis. Specifically, we analyzed expression of CD4, CD8, CD14, CD40, CD86, CD123, HLA-DR, IL-10, LYVE, VEGFR3, and VEGF-C in lymph nodes. We compared sentinel lymph nodes with and without metastasis from patients with melanoma with both infection inflamed (reactive) and dormant human lymph nodes. There were no differences demonstrated between sentinel lymph nodes with or without metastasis from patients with melanoma in any of the markers that were tested. Both groups of sentinel lymph nodes had fewer CD8 T cells than either set of control nodes. Whereas the infection inflamed lymph nodes demonstrated Th2 polarity, the dormant lymph nodes demonstrated Th1 polarity. In conclusion, changes in regional immunity appeared to precede metastasis in melanoma. Whether there was tumor present in sentinel lymph nodes or not, these nodes demonstrated a marked decrease in cytotoxic T cells compared with both sets of controls. Furthermore, the control lymph nodes used for comparison can significantly impact interpretation, as the dormant and reactive lymph nodes markedly varied in their immune profiles. These immunologic changes may explain the successful metastasis of melanoma in the midst of the immune environment of the sentinel lymph node, and lend insights into the mechanisms of lymphatic metastases in other solid malignancies. © 2011 USCAP, Inc. All rights reserved.
Rausch S.M.,H. Lee Moffitt Cancer Center and Research Institute |
Clark M.M.,Mayo Medical School |
Patten C.,Mayo Medical School |
Liu H.,Cancer Center Statistics |
And 4 more authors.
Cancer | Year: 2010
BACKGROUND: Previous research has demonstrated that many lung cancer survivors report difficulties with symptom control and experience a poor quality of life (QOL). Although recent studies have suggested a relationship of single nucleotide polymorphisms (SNPs) in several cytokine genes with cancer susceptibility and prognosis, associations with symptom burden and QOL have not been examined. The current study was conducted to identify SNPs related to symptom burden and QOL outcomes in lung cancer survivors. METHODS: All participants were enrolled in the Mayo Clinic Lung Cancer Cohort following diagnosis of lung cancer. A total of 1149 Caucasian lung cancer survivors completed questionnaires and had genetic samples available. The main outcome measures were symptom burden as measured by the Lung Cancer Symptom Scale and health-related QOL as measured by the Short-Form General Health Survey. RESULTS: Twenty-one SNPs in cytokine genes were associated with symptom burden and QOL outcomes. Our results suggested both specificity and consistency of cytokine gene SNPs in predicting outcomes. CONCLUSIONS: These results provide support for genetic predisposition to QOL and symptom burden and may aid in identification of lung cancer survivors at high risk for symptom management and QOL difficulties. © 2010 American Cancer Society.
Kadakia K.C.,Mayo Medical School |
Barton D.L.,Mayo Medical School |
Loprinzi C.L.,Mayo Medical School |
Sloan J.A.,Mayo Medical School |
And 6 more authors.
Cancer | Year: 2012
Background: Chemoprevention with systemic retinoids has demonstrated promise in decreasing the incidence of new primary nonmelanoma skin cancers (NMSCs) in immunocompromised post-transplantation recipients. There is limited evidence for the use of systemic retinoids in the nontransplantation patient. To the authors' knowledge, this is the first randomized controlled trial to assess the efficacy of acitretin as a chemopreventive agent in nontransplantation patients at high-risk for NMSC. Methods: The study was designed as a prospective, randomized, double-blind, placebo-controlled clinical trial. To test the possible skin cancer-preventing effect of a 2-year treatment with acitretin, 70 nontransplantation patients aged >yen;18 years who had a history of >yen;2 NMSCs within 5 years of trial onset were randomized to receive either placebo or acitretin 25 mg orally 5 days per week. The primary outcome measure was the rate of new NMSC development. Results: Seventy patients were randomized to receive either acitretin alone (N = 35) or placebo (N = 35). During the 2-year treatment period, the patients who received acitretin did not have a statistically significant reduction in the rate of new primary NMSCs (odds ratio, 0.41; 95% confidence interval, 0.15-1.13; 54% vs 74%; P =.13). However, using the incidence of new NMSC, the time to new NMSC, and total NMSC counts, an umbrella test indicated a significant trend that favored the use of acitretin (chi-square statistic, 3.94; P =.047). The patients who received acitretin reported significantly more mucositis and skin toxicities compared with the patients who received placebo. Conclusions: Although there was not a statistically significant benefit observed with the use of acitretin, this may have been the result of low statistical power. © 2011 American Cancer Society.
Benzo R.,Mayo Medical School |
Wigle D.,Mayo Medical School |
Novotny P.,Cancer Center Statistics |
Wetzstein M.,Mayo Medical School |
And 4 more authors.
Lung Cancer | Year: 2011
Complete surgical resection is the most effective curative treatment for lung cancer. However, many patients with lung cancer also have severe COPD which increases their risk of postoperative complications and their likelihood of being considered " inoperable." Preoperative pulmonary rehabilitation (PR) has been proposed as an intervention to decrease surgical morbidity but there is no established protocol and no randomized study has been published to date.We tested two preoperative PR interventions in patients undergoing lung cancer resection and with moderate-severe COPD in a randomized single blinded design. Outcomes were length of hospital stay and postoperative complications.The first study tested 4 weeks of guideline-based PR vs. usual care: that study proved to be very difficult to recruit as patients and providers were reluctant to delay surgery. Nine patients were randomized and no differences were found between arms.The second study tested ten preoperative PR sessions using a customized protocol with nonstandard components (exercise prescription based on self efficacy, inspiratory muscle training, and the practice of slow breathing) (n=10) vs. usual care (n=9). The PR arm had shorter length of hospital stay by 3 days (p=0.058), fewer prolonged chest tubes (11% vs. 63%, p=0.03) and fewer days needing a chest tube (8.8 vs. 4.3 days p=0.04) compared to the controlled arm.A ten-session preoperative PR intervention may improve post operative lung reexpansion evidenced by shorter chest tube times and decrease the length of hospital stay, a crude estimator of post operative morbidity and costs. Our results suggest the potential for short term preoperative pulmonary rehabilitation interventions in patients with moderate-severe COPD undergoing curative lung resection. 4 weeks of conventional preoperative PR seems non feasible. © 2011 Elsevier Ireland Ltd.
Swetz K.M.,Mayo Medical School |
Shanafelt T.D.,Mayo Medical School |
Drozdowicz L.B.,Mayo Medical School |
Sloan J.A.,Cancer Center Statistics |
And 4 more authors.
Journal of Heart and Lung Transplantation | Year: 2012
Background: Pulmonary arterial hypertension (PAH) is a complex disease with variable clinical manifestations; nevertheless, morbidity and mortality associated with PAH are considerable. This study examined quality of life (QOL) in PAH patients and assessed use of palliative care (PC) for addressing QOL issues and what barriers might exist regarding early PC implementation for patients with PAH. Methods: An Internet-based survey was distributed to Pulmonary Hypertension Association patient-related listservs. Symptom burden and QOL were assessed using Linear Analog Self Assessment (LASA) QOL items and the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR). Results: Of 774 eligible patients with active e-mail addresses, 315 returned surveys (41% overall response), and 276 (88%) contained analyzable responses. Responders (mean age, 48.9 years ± 16.0) were predominantly white (85%), female (86%), and with idiopathic PAH (42%). Profound deficiency in overall QOL (40%), fatigue (57%), physical well-being (56%), social activity (49%), emotional well-being (49%), and pain (38%) were reported. Most patients believed their PAH physician had excellent understanding of PAH progression/plan of care (92%), but less were satisfied with care regarding QOL management (77%). Few patients considered PC (8%), or had pain management (4%) or PC involved (1%). Most common reasons were beliefs that patients were doing well/not sick (63%) or that PC had not been suggested (22%). Conclusions: PAH may result in symptoms or QOL impairment persisting despite optimal PAH therapy. However, PC awareness or use by PAH patients and providers is low. Opportunities may exist to integrate PC into care for PAH patients. © 2012 International Society for Heart and Lung Transplantation.