Validation of metastasis-free survival as a surrogate endpoint for overall survival in localized prostate cancer in the era of docetaxel for castration-resistant prostate cancer.

BACKGROUND: Prior work from the Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) consortium (ICECaP-1) demonstrated that metastasis-free survival (MFS) is a valid surrogate for overall survival (OS) in localized prostate cancer (PCa). This was based on data from patients treated predominantly before 2004, prior to docetaxel being available for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). We sought to validate surrogacy in a more contemporary era (ICECaP-2) with greater availability of docetaxel and other systemic therapies for mCRPC. PATIENTS AND METHODS: Eligible trials for ICECaP-2 were those providing individual patient data (IPD) after publication of ICECaP-1 and evaluating adjuvant/salvage therapy for localized PCa, and which collected MFS and OS data. MFS was defined as distant metastases or death from any cause, and OS was defined as death from any cause. Surrogacy was evaluated using a meta-analytic two-stage validation model, with an R2 ≥ 0.7 defined a priori as clinically relevant. RESULTS: A total of 15 164 IPD from 14 trials were included in ICECaP-2, with 70% of patients treated after 2004. The median follow-up was 8.3 years and the median postmetastasis survival was 3.1 years in ICECaP-2, compared with 1.9 years in ICECaP-1. For surrogacy condition 1, Kendall's tau was 0.92 for MFS with OS at the patient level, and R2 from weighted linear regression (WLR) of 8-year OS on 5-year MFS was 0.73 (95% confidence interval 0.53-0.82) at the trial level. For condition 2, R2 was 0.83 (95% confidence interval 0.64-0.89) from WLR of log[hazard ratio (HR)]-OS on log(HR)-MFS. The surrogate threshold effect on OS was an HR(MFS) of 0.81. CONCLUSIONS: MFS remained a valid surrogate for OS in a more contemporary era, where patients had greater access to docetaxel and other systemic therapies for mCRPC. This supports the use of MFS as the primary outcome measure for ongoing adjuvant trials in localized PCa.

Tobacco use in first-episode psychosis, a multinational EU-GEI study.

BACKGROUND: Tobacco is a highly prevalent substance of abuse in patients with psychosis. Previous studies have reported an association between tobacco use and schizophrenia. The aim of this study was to analyze the relationship between tobacco use and first-episode psychosis (FEP), age at onset of psychosis, and specific diagnosis of psychosis. METHODS: The sample consisted of 1105 FEP patients and 1355 controls from the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. We assessed substance use with the Tobacco and Alcohol Questionnaire and performed a series of regression analyses using case-control status, age of onset of psychosis, and diagnosis as outcomes and tobacco use and frequency of tobacco use as predictors. Analyses were adjusted for sociodemographic characteristics, alcohol, and cannabis use. RESULTS: After controlling for cannabis use, FEP patients were 2.6 times more likely to use tobacco [p ⩽ 0.001; adjusted odds ratio (AOR) 2.6; 95% confidence interval (CI) [2.1-3.2]] and 1.7 times more likely to smoke 20 or more cigarettes a day (p = 0.003; AOR 1.7; 95% CI [1.2-2.4]) than controls. Tobacco use was associated with an earlier age at psychosis onset (ß = -2.3; p ⩽ 0.001; 95% CI [-3.7 to -0.9]) and was 1.3 times more frequent in FEP patients with a diagnosis of schizophrenia than in other diagnoses of psychosis (AOR 1.3; 95% CI [1.0-1.8]); however, these results were no longer significant after controlling for cannabis use. CONCLUSIONS: Tobacco and heavy-tobacco use are associated with increased odds of FEP. These findings further support the relevance of tobacco prevention in young populations.

Clinical outcomes in men of diverse ethnic backgrounds with metastatic castration-resistant prostate cancer.

BACKGROUND: We have shown previously in multivariable analysis that black men had 19% lower risk of death than white men with metastatic castration-resistant prostate cancer (mCRPC) treated with a docetaxel and prednisone (DP)-based regimen. The primary goal of this analysis was to compare progression-free survival (PFS), biochemical PFS, ≥50% decline in prostate-specific antigen (PSA) from baseline and objective response rate (ORR) in white, black and Asian men with mCRPC treated with a DP-based regimen. PATIENTS AND METHODS: Individual patient data from 8820 mCRPC men randomized on nine phase III trials to a DP-containing regimen were combined. Race used in the analysis was based on self-report. End points were PFS, biochemical PSA, ≥50% decline in PSA from baseline and ORR. The proportional hazards and the logistic regression models were employed to assess the prognostic importance of race in predicting outcomes adjusting for established prognostic factors. RESULTS: Of 8820 patients, 7528 (85%) were white, 500 (6%) were black, 424 were Asian (5%) and 368 (4%) had race unspecified. Median PFS were 8.3 [95% confidence interval (CI) 8.2-8.5], 8.2 (95% CI 7.4-8.8) and 8.3 (95% CI 7.6-8.8) months in white, black and Asian men, respectively. Median PSA PFS were 9.9 (95% CI 9.7-10.4), 8.5 (95% CI 8.0-10.3) and 11.1 (95% CI 9.9-12.5) months in white, black and Asian men, respectively. CONCLUSIONS: We observed no differences in clinical outcomes by race and ethnic groups in men with mCRPC enrolled on these phase III clinical trials with DP.

Influence of social cognition as a mediator between cognitive reserve and psychosocial functioning in patients with first episode psychosis.

BACKGROUND: Social cognition has been associated with functional outcome in patients with first episode psychosis (FEP). Social cognition has also been associated with neurocognition and cognitive reserve. Although cognitive reserve, neurocognitive functioning, social cognition, and functional outcome are related, the direction of their associations is not clear. Therefore, the main aim of this study was to analyze the influence of social cognition as a mediator between cognitive reserve and cognitive domains on functioning in FEP both at baseline and at 2 years. METHODS: The sample of the study was composed of 282 FEP patients followed up for 2 years. To analyze whether social cognition mediates the influence of cognitive reserve and cognitive domains on functioning, a path analysis was performed. The statistical significance of any mediation effects was evaluated by bootstrap analysis. RESULTS: At baseline, as neither cognitive reserve nor the cognitive domains studied were related to functioning, the conditions for mediation were not satisfied. Nevertheless, at 2 years of follow-up, social cognition acted as a mediator between cognitive reserve and functioning. Likewise, social cognition was a mediator between verbal memory and functional outcome. The results of the bootstrap analysis confirmed these significant mediations (95% bootstrapped CI (-10.215 to -0.337) and (-4.731 to -0.605) respectively). CONCLUSIONS: Cognitive reserve and neurocognition are related to functioning, and social cognition mediates in this relationship.

Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) 2015.

The first St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) Expert Panel identified and reviewed the available evidence for the ten most important areas of controversy in advanced prostate cancer (APC) management. The successful registration of several drugs for castration-resistant prostate cancer and the recent studies of chemo-hormonal therapy in men with castration-naïve prostate cancer have led to considerable uncertainty as to the best treatment choices, sequence of treatment options and appropriate patient selection. Management recommendations based on expert opinion, and not based on a critical review of the available evidence, are presented. The various recommendations carried differing degrees of support, as reflected in the wording of the article text and in the detailed voting results recorded in supplementary Material, available at Annals of Oncology online. Detailed decisions on treatment as always will involve consideration of disease extent and location, prior treatments, host factors, patient preferences as well as logistical and economic constraints. Inclusion of men with APC in clinical trials should be encouraged.

Clinical symptoms and personality traits predict subpopulations of treatment-seeking substance users.

BACKGROUND: The heterogeneity of treatment-seeking substance users represents a challenge, as most studies include participants having problems with specific substances or merge polysubstance users into the same category without considering differences between profiles. Considering the inconsistent literature on predictors of treatment outcomes, this study aimed to identify subpopulations of individuals with substance use disorders (SUDs) and analyze the association among class membership, previous relapses, and treatment retention. METHODS: The study recruited a total of 159 participants (mean age = 40.60, SD = 8.70; 85.5% males) from two treatment facilities (outpatient daycare and inpatient residential centers). The baseline assessment gathered lifetime and current substance use, and personality and psychopathology measures. The study performed a latent class analysis to identify subpopulations of substance users and explored predictors of class membership using a multinomial regression analysis. RESULTS: The study found six different classes of substance users based on their diagnosis and pattern of substance use: class 1 (6.92% of participants): individuals with cannabis as primary substance, alcohol/cocaine as secondary substance and additional use of stimulants or other drugs; class 2 (30.82%): cocaine as primary substance, alcohol as secondary and additional cannabis use; class 3 (20.13%): alcohol as primary substance, cocaine as secondary and additional cannabis use; class 4 (17.61%): cocaine as primary substance, cannabis as secondary and additional alcohol/other drugs use; class 5 (16.35%): alcohol as primary and cannabis as secondary substance; class 6 (8.18%): heroin as primary substance, cocaine as secondary and additional alcohol use. Several traits and clinical symptoms predicted distinct class memberships. Participants pertaining to class 6 presented the highest number of relapses (M = 2.54, SD = 1.56). CONCLUSIONS: These results have several clinical implications. Belonging to class 6 was associated with a greater number of previous relapses. Also, specific psychopathological symptoms and personality traits may impact SUD treatment response, which may help clinicians to guide initial assessment and treatment allocation.

Development and validation of circulating tumour cell enumeration (Epic Sciences) as a prognostic biomarker in men with metastatic castration-resistant prostate cancer.

PURPOSE: To evaluate the prognostic significance of circulating tumour cell (CTC) number determined on the Epic Sciences platform in men with metastatic castration-resistant prostate cancer (mCRPC) treated with an androgen receptor signalling inhibitor (ARSI). PATIENTS AND METHODS: A pre-treatment blood sample was collected from men with progressing mCRPC starting either abiraterone or enzalutamide as a first-, second- or third-line systemic therapy at Memorial Sloan Kettering Cancer Center (Discovery cohort, N = 171) or as a first- or second-line therapy as part of the multicenter PROPHECY trial (NCT02269982) (Validation cohort, N = 107). The measured CTC number was then associated with overall survival (OS) in the Discovery cohort, and progression-free survival (PFS) and OS in the Validation cohort. CTC enumeration was also performed on a concurrently obtained blood sample using the CellSearch® Circulating Tumor Cell Kit. RESULTS: In the MSKCC Discovery cohort, CTC count was a statistically significant prognostic factor of OS as a dichotomous (<3 CTCs/mL versus ≥ 3 CTCs/mL; hazard ratio [HR] = 1.8 [95% confidence interval {CI} 1.3-3.0]) and a continuous variable when adjusting for line of therapy, presence of visceral metastases, prostate-specific antigen, lactate dehydrogenase and alkaline phosphatase. The findings were validated in an independent datas et from PROPHECY (HR [95% CI] = 1.8 [1.1-3.0] for OS and 1.7 [1.1-2.9] for PFS). A strong correlation was also observed between CTC counts determined in matched samples on the CellSearch® and Epic platforms (r = 0.84). CONCLUSION: The findings validate the prognostic significance of pretreatment CTC number determined on the Epic Sciences platform for predicting OS in men with progressing mCRPC starting an ARSI.

Efficacy of carboplatin-taxane combinations in the management of castration-resistant prostate cancer: a pooled analysis of seven prospective clinical trials.

BACKGROUND: Docetaxel is associated with prolonged survival in castration-resistant prostate cancer (CRPC). Platinum compounds have modest but distinct single-agent activity. Carboplatin may have greatest potential for benefit when combined with taxanes. We investigated whether there is a subset of patients with CRPC for whom the efficacy of combination taxane-estramustine-carboplatin (TEC) chemotherapy may be greatest. PATIENTS AND METHODS: Individual patient data (n = 310) were obtained from seven trials using TEC chemotherapy. Prostate-specific antigen (PSA) response was defined as > or = 50% post-therapy decline from baseline. Overall survival was defined from baseline to death from any cause. Logistic and Cox regression were used to investigate heterogeneity in outcome to TEC by patient and disease characteristics. Predicted survival probabilities were calculated from the Halabi Cancer and Leukemia Group B (CALGB) nomogram. RESULTS: The pooled PSA response proportion was 69% [95% confidence interval (CI) 56% to 80%]. There was no evidence of differential PSA response by disease characteristics. Established prognostic factors were associated with survival. The pooled 12-month survival estimate of 79% (95% CI 71% to 84%) was higher than the median 59% 12-month nomogram-predicted survival. CONCLUSIONS: TEC chemotherapy has significant clinical activity in CRPC. A randomized, controlled trial evaluating the addition of carboplatin to taxane-based chemotherapy is needed to elucidate the value of carboplatin in CRPC.

A phase II trial of cisplatin (C), gemcitabine (G) and gefitinib for advanced urothelial tract carcinoma: results of Cancer and Leukemia Group B (CALGB) 90102.

BACKGROUND: This phase II trial (Cancer and Leukemia Group B 90102) sought to determine the efficacy of cisplatin, standard infusion of gemcitabine and gefitinib in patients with advanced urothelial carcinoma. PATIENTS AND METHODS: Eligible patients had previously untreated measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status of zero to two and creatinine clearance >50 ml/min. Treatment consisted of cisplatin 70 mg/m(2) day 1 and gemcitabine 1000 mg/m(2) on days 1 and 8 given every 3 weeks concurrent with gefitinib 500 mg/day orally for six cycles. Maintenance gefitinib 500 mg/day was continued for responding or stable disease. RESULTS: Fifty-four of 58 patients were assessable. Twelve patients (22%) had node-only disease, and 25 (46%) had an ECOG performance status of zero. There were 23 objective responses for an overall response rate of 42.6% [95% confidence interval (CI) 29.2% to 56.8%]. The median survival time was 15.1 months (95% CI 11.1-21.7 months) and the median time to progression was 7.4 months (95% CI 5.6-9.2 months). CONCLUSIONS: The combination of cisplatin, gemcitabine and gefitinib is well tolerated and active in advanced transitional cell carcinoma. The addition of gefitinib does not appear to improve response rate or survival in comparison to historical controls of cisplatin and gemcitabine alone.

The evolution and understanding of skeletal complication endpoints in clinical trials of tumors with metastasis to the bone.

Bone metastases are a frequent complication of solid tumors, leading to significant skeletal sequelae that negatively impact quality of life and survival. Prevention and management of skeletal-related complications are critical treatment goals in oncology. Endpoints used in clinical trials to evaluate skeletal-related complications have evolved. In contrast to single measures of bone health, contemporary clinical trial endpoints reflect composite measures of skeletal-related complications, and increasingly also survival. In addition, key symptomatic components, which are more reflective of quality of life and the patient experience, are being incorporated. Given the evolution and resulting diversity of the endpoints being used in pivotal trials, it is becoming increasingly relevant to clarify the utility and the potential clinical impact of these measures not only within the context of trials but also in the real-world setting. Here, we describe the development and evolution of skeletal endpoints used in trials, and discuss their clinical relevance.

Phase II study of bortezomib in patients with previously treated advanced urothelial tract transitional cell carcinoma: CALGB 90207.

BACKGROUND: There is no standard second-line treatment for advanced urothelial carcinoma (UC). Response rates to second-line chemotherapy for advanced UC are low and response duration is short. Bortezomib is a proteasome inhibitor with preclinical activity against UC. PATIENTS AND METHODS: Treatment consisted of bortezomib 1.3 mg/m(2) i.v. twice weekly for two consecutive weeks, followed by a 1-week break. The primary end point was objective response rate (complete response + partial response) by Response Evaluation Criteria in Solid Tumors criteria. Secondary end points included safety, toxicity, and progression-free and overall survival. RESULTS: In all, 25 patients with advanced UC previously treated with combination chemotherapy were enrolled in a multi-institutional single-arm trial from December 2003 through April 2005. Only 29% of patients had node-only metastases. Grade 3/4 drug-related toxic effects included thrombocytopenia (4%), anemia (8%), lymphopenia (8%), sensory neuropathy (6%), hyperglycemia (4%), hypernatremia (4%), fatigue (4%), neuropathic pain (6%), dehydration (4%), and vomiting (4%). No objective responses were observed [95% confidence interval (CI) = 0-12]. The median time to progression was 1.4 months (95% CI = 1.1-2.0 months), and the median survival time was 5.7 months (95% CI = 3.6-8.4 months). There were no treatment-related deaths. CONCLUSION: Although bortezomib is well tolerated, it does not have antitumor activity as second-line therapy in UC.

Comparison of air exhausts for surgical body suits (space suits) and the potential for periprosthetic joint infection.

BACKGROUND: Periprosthetic joint infection is a major complication of total joint replacement surgery and is associated with significant morbidity, mortality and financial burden. Surgical body suits (space suits), originally designed to reduce the incidence of infection, have paradoxically been implicated in increased periprosthetic joint infection rates recently. Air exhausted from space suits may contribute to this increased rate of periprosthetic joint infection. AIM: To investigate the flow of air exhausted from space suits commonly used in modern operating theatres. METHODS: The exhaust airflow patterns of four commercially available space suit systems were compared using a fog machine and serial still photographs. FINDINGS: The space suit systems tested all air exhausted into the operating room. The single fan systems with a standard surgical gown exhausted air laterally from the posterior gown fold at approximately the level of the surgical field. The single fan system with a dedicated zippered suit exhausted air at a level below the surgical field. The dual fan system exhausted air out of the top of the helmet at a level above the surgical field. CONCLUSIONS: Space suit systems currently in use in joint replacement surgery differ significantly from traditional body exhaust systems; rather than removing contaminated air from the operating environment, modern systems exhaust this air into the operating room, in some cases potentially towards the sterile instrument tray and the surgical field.

Validation of a breast cancer risk assessment model in women with a positive family history.

BACKGROUND: Gail et al. developed a statistical model for estimating the risk of developing breast cancer in white women screened annually with mammography. This model is used for counseling and for admission to clinical trials. PURPOSE: We evaluated the model prospectively in a cohort of women with a family history of breast cancer. METHODS: We followed women who participated in the American Cancer Society 1987 Texas Breast Screening Project. The model was evaluated by comparing the observed (O) and expected (E) numbers of breast cancers using composite background rates from both the Breast Cancer Detection and Demonstration Project and the Surveillance, Epidemiology, and End Results program of the National Cancer Institute. Data were partitioned by adherence to American Cancer Society screening guidelines. RESULTS: The Gail et al. model predicted the risk well among women who adhered to the American Cancer Society guidelines (O/E = 1.12; 95% confidence interval = 0.75-1.61) but overpredicted risk for women who did not adhere to the guidelines. There was an indication that the model overpredicted risk for women younger than 60 years old and underpredicted risk in women aged 60 years and older. CONCLUSIONS: Overall, the Gail et al. model accurately predicts risk in women with a family history of breast cancer and who adhere to American Cancer Society screening guidelines. Thus, the model should be used as it was intended, for women who receive annual mammograms.

Frequent detection of bcl-2/JH translocations in human blood and organ samples by a quantitative polymerase chain reaction assay.

Using an ultrasensitive assay involving the PCR, we have examined the frequency of a follicular lymphoma-associated translocation in peripheral blood from 132 individuals, most of whom were healthy blood donors. This translocation occurs between the bcl-2 proto-oncogene and the JH gene region and prolongs the life of lymphocytes. At a level of sensitivity of 1 translocation-bearing cell per 5 x 10(6) cells, almost one-half of healthy human adults had this translocation in the mononuclear fraction of peripheral blood. However, the range of frequency of these translocations spanned almost three orders of magnitude among translocation-positive individuals. Furthermore, there was a statistically significant increase with age in the percentage of individuals who were translocation positive. Such an age correlation was also seen for the percentage of blood donors with rather high translocation frequencies (> or = 20 per 5 x 10(6) peripheral blood mononuclear cells). However, the blood donor who had by far the highest concentration of this translocation was a healthy 35-year-old male containing approximately 900 apparently monoclonal, translocation-bearing cells per 5 x 10(6) peripheral blood mononuclear cells. Our findings suggest that some individuals who may be at risk for follicular lymphoma might be able to be identified by this PCR assay on peripheral blood. Also, these data may help explain the age dependence of the occurrence of this cancer.

Vascular endothelial growth factor and basic fibroblast growth factor urine levels as predictors of outcome in hormone-refractory prostate cancer patients: a cancer and leukemia group B study.

Better prognostic markers are needed for hormone-refractory prostate cancer (HRPC) patients. No single biochemical or clinical parameter can reliably predict patient response to therapy or rapidity of disease progression. Peptide factors involved in major cancer growth pathways, such as tumor angiogenesis, are attractive candidates as markers of low- and high-risk HRPC patients. We analyzed prospectively collected urine specimens from 100 of 390 HRPC patients undergoing therapy with the growth factor antagonist suramin as part of CALGB 9480. Levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were assessed from day 1 of therapy (D1) and day 29 (D29) urine samples from this subset of 100 randomly selected patients. Growth factor levels were determined by standardized ELISA microtiter plate assays from a commercial (bFGF) or proprietary (VEGF) source. Pretreatment urine VEGF levels were predictive of survival. In univariate analysis, patients whose baseline urine VEGF level was < or =28 pg/ml (the median level) had an average survival of 17 months; those with baseline VEGF >28 pg/ml had a significantly shorter survival of 10 months (P = 0.024). This difference corresponded to a 60% increased risk of dying for the higher urine VEGF patients (hazard ratio, 1.62; P = 0.03) and remained significant in multivariate analysis (hazard ratio, 1.72, P = 0.02). No significant correlations between urine bFGF level or change in bFGF levels and survival were found. These results support the notion that certain peptide growth factor-mediated, mitogenic pathways are important in HRPC and that their levels can predict outcome.

Evaluation of an epithelial plasticity biomarker panel in men with localized prostate cancer.

BACKGROUND: Given the potential importance of epithelial plasticity (EP) to cancer metastasis, we sought to investigate biomarkers related to EP in men with localized prostate cancer (PC) for the association with time to PSA recurrence and other clinical outcomes after surgery. METHODS: Men with localized PC treated with radical prostatectomy at the Durham VA Medical Center and whose prostatectomy tissues were included in a tissue microarray (TMA) linked to long-term outcomes. We performed immunohistochemical studies using validated antibodies against E-cadherin and Ki-67 and mesenchymal biomarkers including N-cadherin, vimentin, SNAIL, ZEB1 and TWIST. Association studies were conducted for each biomarker with baseline clinical/pathologic characteristics an risk of PSA recurrence over time. RESULTS: Two hundred and five men contributed TMA tissue and had long-term follow-up (median 11 years). Forty-three percent had PSA recurrence; three died of PC. The majority had high E-cadherin expression (86%); 14% had low/absent E-cadherin expression. N-cadherin was rarely expressed (<4%) and we were unable to identify an E-to-N-cadherin switch as independently prognostic. No associations with clinical risk group, PSA recurrence or Gleason sum were noted for SNAIL, ZEB1, vimentin or TWIST, despite heterogeneous expression between patients. We observed an association of higher Ki-67 expression with Gleason sum (P=0.043), National Comprehensive Cancer Network risk (P=0.013) and PSA recurrence (hazard ratio 1.07, P=0.016). CONCLUSIONS: The expression of EP biomarkers in this cohort of men with a low risk of PC-specific mortality was not associated with aggressive features or PSA relapse after surgery.