Combined Survival Analysis Research Articles

Abstract 4715: OX40 expression improves the prognostic value of CD8 positive lymphocyte density in colorectal carcinoma

Abstract Background: The prognostic role of the immunological microenvironment in colorectal cancer (CRC) is well known. Among immune cell types, CD8 positive T lymphocyte infiltration is an established prognostic marker clearly associated with a favorable clinical course of the disease. In contrast, there is limited information about the prognostic role of OX40 positive immune cell infiltration in CRC. However, increasing evidence suggests that OX40 positive immune cell infiltration, as a single biomarker, has a positive prognostic effect in CRC patients. To the best of our knowledge, the impact of the combination of OX40 positive immune cells and CD8 positive T lymphocytes is unknown. Methods: A tissue microarray composed of 441 biopsies was evaluated for OX40 positive immune cells and CD8 positive T lymphocyte infiltration by immunohistochemistry. The intratumoral number of tumor infiltrating cells positive for OX40 and CD8 antigens was evaluated by 2 independent investigators achieving an optimal concordance rate of 90%. According to the frequency and staining intensity, we identified four subgroups of cell population: OX40low/CD8low, OX40high/CD8low, OX40low/CD8high and OX40high/CD8high. They were correlated with clinicopathological data, and a combined survival analysis was performed. Results: The mean age of the patients cohort was 69.9 ±10.7 years. A total of 230 (52%) biopsies were from female and 211 (48%) from male CRC patients. Both, OX40 and CD8 positive cell infiltration had a significant, prognostic impact on the clinical outcome of the disease as individual markers (p<0.0001 and p=0.007, respectively). Remarkably, the combination of OX40 and CD8 positive cell infiltration (OX40high/CD8high), significantly enhanced the overall survival of these patients (p<0.0001). These results were maintained after a multivariate Cox regression analysis including T and N stages, grade, vascular invasion, tumor border configuration, microsatellite stability and CD8 and OX40 positive cell infiltration suggesting that this combination is an independent prognostic factor in CRC patients. Conclusion: The combination OX40 and CD8 positive cell infiltration significantly enhances the overall survival compared to OX40 and CD8 positive cell infiltration alone. OX40high/CD8high positive cell infiltration is an independent, favorable, prognostic marker in CRC. Citation Format: Benjamin Weixler, Raoul A. Droeser, Roberto Sorge, Tarik Delko, Christian A. Nebiker, Giandomenica Iezzi, Giulio C. Spagnoli, Christoph Kettelhack, Urs W. von Holzen, Daniel Oertli, Luigi Terracciano, Luigi Tornillo, Giuseppe Sconocchia. OX40 expression improves the prognostic value of CD8 positive lymphocyte density in colorectal carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4715. doi:10.1158/1538-7445.AM2014-4715

Combined survival analysis of cardiac patients by a Cox PH model and a Markov chain

The control and treatment of dyslipidemia is a major public health challenge, particularly for patients with coronary heart diseases. In this paper we propose a framework for survival analysis of patients who had a major cardiac event, focusing on assessment of the effect of changing LDL-cholesterol level and statins consumption on survival. This framework includes a Cox PH model and a Markov chain, and combines their results into reinforced conclusions regarding the factors that affect survival time. We prospectively studied 2,277 cardiac patients, and the results show high congruence between the Markov model and the PH model; both evidence that diabetes, history of stroke, peripheral vascular disease and smoking significantly increase hazard rate and reduce survival time. On the other hand, statin consumption is correlated with a lower hazard rate and longer survival time in both models. The role of such a framework in understanding the therapeutic behavior of patients and implementing effective secondary and primary prevention of heart diseases is discussed here.

Inhibition of the Inflammatory Cytokine TNF-α Increases Adenovirus Activity in Ovarian Cancer via Modulation of cIAP1/2 Expression

Oncolytic adenoviruses show promise as a cancer treatment. However, they generate acute inflammatory responses with production of cytokines, including tumor necrosis factor-α (TNF-α). We investigated whether inhibition of TNF-α augments efficacy of the E1A CR2-deleted adenovirus dl922-947 in ovarian cancer. dl922-947 induced transcription of TNF-α and its downstream signaling targets interleukin-6 and -8 (IL-6 and IL-8) in ovarian cancer cells. In vitro, RNAi-mediated knockdown of TNF-α reduced production of multiple inflammatory cytokines after infection and increased ovarian cancer cell sensitivity to virus cytotoxicity, as did treatment with the anti-TNF-α antibody infliximab. In vivo, stable knockdown of TNF-α in IGROV-1 xenografts increased the anticancer activity of dl922-947. In addition, inhibition of TNF-α using monoclonal antibodies also improved dl922-947 efficacy. This increased efficacy resulted from suppression of cellular inhibitor of apoptosis-1 and -2 (cIAP1 and cIAP2) transcription in malignant cells and a consequent increase in caspase-mediated apoptosis. These findings suggest that TNF-α acts as a survival factor in adenovirus-infected cells. Combining TNF-α inhibition with oncolytic adenoviruses could improve antitumor activity in clinical trials.

Tribulations of a prostate cancer trial – Lessons learned from TOAD, a Cancer Council Victoria and Transtasman Radiation Oncology Group trial

From 2004–2009 a total of 226 out of a target of 750 prostate cancer patients have been randomised into the Timing of Androgen Deprivation trial between immediate and delayed androgen deprivation. A screening log was kept by participating centres for the first 928 patients, which documented the reasons for non-entry into the trial; 42.7% of screened patients were ineligible and a further 33.0% were not entered for other reasons. Fewer than 10% of patients cited not wanting to be part of a clinical trial as a reason for non-entry. Strategies to improve recruitment included broadening the eligibility criteria, encouraging international collaboration, the use and support of research nurses in the private health care environment, and the use of phone follow-up. Recruitment will be completed at the number originally intended to inform the interim analysis designed to test the validity of the statistical assumptions, and a combined survival analysis with the Canadian study is planned.

Genetic parameters for social effects on survival in cannibalistic layers: Combining survival analysis and a linear animal model

BackgroundMortality due to cannibalism in laying hens is a difficult trait to improve genetically, because censoring is high (animals still alive at the end of the testing period) and it may depend on both the individual itself and the behaviour of its group members, so-called associative effects (social interactions). To analyse survival data, survival analysis can be used. However, it is not possible to include associative effects in the current software for survival analysis. A solution could be to combine survival analysis and a linear animal model including associative effects. This paper presents a two-step approach (2STEP), combining survival analysis and a linear animal model including associative effects (LAM).MethodsData of three purebred White Leghorn layer lines from Institut de Sélection Animale B.V., a Hendrix Genetics company, were used in this study. For the statistical analysis, survival data on 16,780 hens kept in four-bird cages with intact beaks were used. Genetic parameters for direct and associative effects on survival time were estimated using 2STEP. Cross validation was used to compare 2STEP with LAM. LAM was applied directly to estimate genetic parameters for social effects on observed survival days.ResultsUsing 2STEP, total heritable variance, including both direct and associative genetic effects, expressed as the proportion of phenotypic variance, ranged from 32% to 64%. These results were substantially larger than when using LAM. However, cross validation showed that 2STEP gave approximately the same survival curves and rank correlations as LAM. Furthermore, cross validation showed that selection based on both direct and associative genetic effects, using either 2STEP or LAM, gave the best prediction of survival time.ConclusionIt can be concluded that 2STEP can be used to estimate genetic parameters for direct and associative effects on survival time in laying hens. Using 2STEP increased the heritable variance in survival time. Cross validation showed that social genetic effects contribute to a large difference in survival days between two extreme groups. Genetic selection targeting both direct and associative effects is expected to reduce mortality due to cannibalism in laying hens.

Combined Survival Analysis of Prospective Clinical Trials of Gefitinib for Non–Small Cell Lung Cancer with EGFR Mutations

Somatic mutations of the epidermal growth factor receptor (EGFR) gene are associated with an increased response to gefitinib in patients with non-small cell lung cancer. We have examined the impact of gefitinib on progression-free survival and overall survival in patients with EGFR mutation-positive non-small cell lung cancer. We searched for all clinical trials that prospectively evaluated the efficacy of gefitinib for advanced non-small cell lung cancer with EGFR mutations in Japan. We did a combined analysis based on individual patient data from the identified trials. Seven eligible trials were identified for a total of 148 non-small cell lung cancer patients with EGFR mutations. The overall response rate to gefitinib was 76.4% [95% confidence interval (95% CI), 69.5-83.2]. The median progression-free survival and overall survival were 9.7 months (95% CI, 8.2-11.1) and 24.3 months (95% CI, 19.8-28.2), respectively. Good performance status and chemotherapy-naïve status were significantly associated with a longer progression-free survival or overall survival. Of the 148 patients, 87 received gefitinib as a first-line therapy, whereas 61 received systemic chemotherapy before gefitinib treatment. The median progression-free survival after the start of first-line therapy was significantly longer in the gefitinib-first group than in the chemotherapy-first group (10.7 versus 6.0 months; P < 0.001), whereas no significant difference in median overall survival was apparent between the two groups (27.7 versus 25.7 months; P = 0.782). Gefitinib monotherapy confers substantial clinical benefit in terms of progression-free survival and overall survival in non-small cell lung cancer patients with EGFR mutations. Randomized trials comparing chemotherapy with gefitinib as a first-line treatment are warranted in such patients.

Gefitinib combined survival analysis of the mutation positives from the prospective phase II trials (I-CAMP)

8101 Background: Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with the therapeutic response to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in patients (pts) with advanced non-small cell lung cancer (NSCLC). Several phase II trials of EGFR-TKIs in pts positive for such EGFR mutations have yielded a high response rate and good survival; however, the number of pts enrolled onto those trials was too small to draw any firm conclusion. Methods: We carried out a combined analysis of seven prospective trials conducted in Japan examining the efficacy and safety of gefitinib monotherapy for advanced NSCLC pts with EGFR mutations. In the present study we updated OS and PFS data for the combined survival analysis and examined prognostic factors for OS and PFS using a Cox regression model. Tumor response and gefitinib-related adverse events were also analyzed using the combined data set. Results: A total of 148 pts were combined from the seven trials. The mean age was 64 years (range: 33 to 89 years) and 69% of the patients were women. The patients had stage IIIb (13%), stage IV (60%), or recurrent (26%) disease, and 97% of them had adeno-carcinoma. The patients had a PS of 0 (37%), 1 (49%), 2 (9%), or 3–4 (5%), and 71% were non-smoker. 57% of the patients received gefitinib as their first line of therapy. It was found that median OS and PFS were 24.3 (95% C.I.: 19.8–28.2) months and 9.7months (95% C.I.: 8.2–11.1) months, respectively. Age (p=0.042), histology (p=0.002), and PS (p<0.001) were significantly related to OS. Age (p=0.050), PS (p=0.014), and the number of chemotherapeutic treatments (p=0.021) were significantly related to longer PFS. The combined response rate was 76.4% and only 6% of the patients had progressive disease. Grade 3/4 interstitial lung disease, skin, diarrhea, and liver adverse events were observed in 2.7%, 2.7%, 1.4%, and 8.1% of the pts, respectively. Conclusions: This is the largest analysis of pts with EGFR mutations and demonstrates that gefitinib produces significant antitumor activity and prolonged survival in this selected NSCLC population. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca Japan, Chugai Pharmaceuticals AstraZeneca Japan

Preclinical and Clinical Experience with Fulvestrant (Faslodex) in Postmenopausal Women with Hormone Receptor-Positive Advanced Breast Cancer

Fulvestrant (Faslodex) is a new type of estrogen receptor (ER) antagonist that binds, blocks, and degrades the ER, leading to reduced expression of the progesterone receptor (PgR). Unlike the selective ER modulator tamoxifen, fulvestrant is devoid of any known agonist activity. Fulvestrant has a steroidal structure that competitively binds to the ER with an affinity much greater than that of tamoxifen. After binding to fulvestrant, degradation of the ER is accelerated, ultimately resulting in a reduction in cellular ER. Immunohistochemical studies have demonstrated that a single intramuscular injection of fulvestrant results in a dose-dependent decrease in ER and PgR indices and in Ki-67 expression. At the approved 250 mg dose, the decrease in receptor positivity with fulvestrant treatment was greater than that with tamoxifen. Phase III clinical trials have demonstrated the clinical benefit of fulvestrant in the endocrine treatment of breast cancer. Among patients who progressed during adjuvant or first-line endocrine therapy, fulvestrant was at least as effective as anastrozole as second-line treatment for the primary endpoints of objective response and time to progression, and was well tolerated. After a median follow-up of 24.5 months, a combined survival analysis from two Phase III studies has shown that fulvestrant may be considered similar to anastrozole for time to death (27.4 months versus 27.7 months, respectively). For the first-line therapy of advanced breast cancer in postmenopausal women, fulvestrant was shown to be active and well tolerated in a trial that compared fulvestrant 250 mg once monthly and tamoxifen 20 mg once daily. Treatment with fulvestrant has also demonstrated clinical efficacy among patients who progressed following treatment with tamoxifen followed by nonsteroidal aromatase inhibitors. The efficacy of fulvestrant in sequential endocrine therapy and in combination with other agents appears promising and active investigations are ongoing to explore the clinical potential of this novel antiestrogen.

Heterogeneity of type I diabetes: analysis of monozygotic twins in Great Britain and the United States.

To determine the risk, hazard rate and factors affecting progression to diabetes in monozygotic twins of patients with Type I (insulin-dependent) diabetes mellitus. Prospective analysis was done of two cohorts of non-diabetic monozygotic twins of patients with Type I diabetes from Great Britain (n = 134) and the United States (n = 53). The diabetes-free survival analysis was similar between both cohorts (p = 0.6). The combined survival analysis (n = 187, median follow-up = 17.7 years, range = 0.01-57) at 40 years of discordance estimated a 39% probability of diabetes for the initially discordant twin. Survival analysis with left truncation of data estimated that probability to be 50%. For twins who became concordant (n = 47), the median discordance time was 4.2 years (range 0.4 to 39), exceeding 15 years in 23.4%. Twins of probands diagnosed at 24 years of age or younger had a 38% probability of diabetes by 30 years of discordance, compared with 6% for twins of probands diagnosed after 24 years of age (p = 0.004). The twins of probands diagnosed before 15 years of age had the highest diabetes hazard rate in the first discordance year, decreasing thereafter. By survival analysis, diabetes risk was higher in twins who were heterozygous for DR3-DQ2 and DR4-DQ8 than in twins with neither DR3-DQ2 nor DR4-DQ8 (p < 0.05). Monozygotic twins of patients with Type I diabetes from two different countries had similar rates of progression to diabetes. Whereas most twins did not develop diabetes, 25% of the twins who progressed did so after more than 14 years of discordance. An age-related heterogeneity was observed, with higher progression to diabetes for twins of patients diagnosed at a younger age.

White-Collars and Black Sheep: A Twenty-Year Criminological Follow-Up of White-Collar Ex-Offenders

This paper describes a further analysis of the outcome of a twenty-year criminological follow-up of a consecutive series of 348 male ex-offenders seeking white-collar employment who were offered the services of a specialist employment agency (APEX) in the early 1970s. This analysis shows the value of a more sophisticated statistical analysis which combines survival analysis with smoothing models: this provides new insights into the theoretical understanding of the data. There is evidence that remaining in contact with the organisation, irrespective of whether a suitable job is found, benefits those with around four to twelve previous convictions.

Casodex (bicalutamide) 150-mg monotherapy compared with castration in patients with previously untreated nonmetastatic prostate cancer: results from two multicenter randomized trials at a median follow-up of 4 years

Objectives. To compare the efficacy, tolerability, and quality of life benefits of bicalutamide (Casodex) 150-mg/day monotherapy and castration in previously untreated nonmetastatic (MO) advanced prostate cancer. Methods. A total of 480 patients with Stage T3/T4 nonmetastatic disease randomly received oral bicalutamide 150 mg/day or castration (either bilateral orchiectomy or goserelin acetate [Zoladex] 3.6 mg every 28 days) in a 2:1 ratio in two open multicenter studies (studies 306 and 307). The design of these studies was similar to allow a pooled analysis. Results. In the combined survival analysis, at median follow-up of 202 and 205 weeks in studies 306 and 307, respectively, with 31% of the cases resulting in death, bicalutamide 150-mg monotherapy was statistically equivalent to castration; the risk of death from any cause was 7% less with bicalutamide than with castration (hazard ratio [HR] = 0.93). Data on time to treatment failure and objective progression could not be pooled, as results for these end points differed between the trials. In study 306, bicalutamide 150-mg monotherapy increased time to objective progression (HR = 0.58; P = 0.033) and treatment failure (HR = 0.66; P = 0.074), whereas in study 307, time to progression (HR = 1.35; P = 0.0471) and treatment failure (HR = 1.24; P = 0.097) favored castration. Bicalutamide therapy showed significant advantages over castration for both sexual interest ( P = 0.029) and physical capacity ( P = 0.046). Bicalutamide 150-mg monotherapy was well tolerated. Conclusions. Bicalutamide 150-mg monotherapy provides a similar survival outcome to castration in previously untreated patients with nonmetastatic advanced prostate cancer and confers statistically significant benefits over castration with respect to sexual interest and physical capacity.