The lag time in initiating clinical testing of new drugs in combination with radiation therapy, a significant barrier to progress?

BACKGROUND: The clinical development of new drugs with radiation appears to be limited. We hypothesised that phase I clinical trials with radiation therapy (RT) are initiated too late into a new drug's lifetime, impeding the ability to complete RT-drug development programmes before patent expiration. METHODS: We identified novel drug-radiation phase I combination trials performed between 1980 and 2012 within the PubMed and ClinicalTrials.gov databases. Data gathered for each drug included: date the initial phase I trial with/without RT was opened/published, date of the published positive phase III trials, and patent expiration dates. Lag time was defined as the interval between opening of the phase I trial without RT and the opening of the phase I with RT. Linear regression was used to model how the lag time has changed over time. RESULTS: The median lag time was 6 years. The initial phase I trial with RT was typically published 2 years after the first published positive phase III trial and 11 years before patent expiration. Using a best-fit linear model, lag time decreased from 10 years for phase I trials published in 1990 to 5 years in 2005 (slope significantly non-zero, P<0.001). CONCLUSIONS: Clinical drug development with RT commences late in the life cycle of anti-cancer agents. Taking into account the additional time required for late-phase clinical trials, the delay in initiating clinical testing of drug-RT combinations discourages drug companies from further pursuing RT-based development. Encouragingly, lag time appears to be decreasing. Further reduction in lag time may accelerate RT-based drug development, potentially improving patient outcomes.

Cancer of unknown primary: a population-based analysis of temporal change and socioeconomic disparities.

BACKGROUND: Cancer of unknown primary (CUP) is the fourth most common cause of cancer death. With advanced diagnostics and treatments, we investigated the proportion of cancers diagnosed as CUP, treatment outcomes and association with socioeconomic disparities. METHODS: We analysed trends in CUP diagnosis and outcome within the Surveillance, Epidemiology, and End Results registry between 1973 and 2008. RESULTS: The percentage of all cancers diagnosed as CUP has decreased over time comprising <2% of cancers since 2007. A higher proportion of CUP was diagnosed in the elderly, females, blacks and residents of less affluent or less educated counties. Median survival of all CUP patients was 3 months, with no improvement over time. The 5-year survival significantly improved in those with squamous histology (squamous cell carcinoma; SCC) but only marginally in non-SCC. Factors associated with a longer survival on multivariate analysis included white race; female; <65 years old; most recent decade at diagnosis; SCC; married; a histological diagnosis; and treatment with radiotherapy (all P<0.001). Despite the improvement in survival with radiotherapy, its use was less frequent in females and blacks. CONCLUSION: The percentage of cancers diagnosed as CUP is decreasing but prognosis remains poor, particularly in non-SCC CUP. However, significant socioeconomic disparities exist in diagnosis and survival, suggesting inequalities in access to diagnostic investigations and treatment.

Association between metabolic syndrome, diabetes mellitus and prostate cancer risk.

BACKGROUND: The worldwide incidence of diabetes mellitus is rapidly increasing. There is recent interest in the influence of glucose metabolism on oncogenesis. We investigated the role of diabetes mellitus and the metabolic syndrome (MS) on prostate cancer development. METHODS: This study consisted of 11 541 men with coronary heart disease screened to participate in a secondary cardiac prevention trial. MS was defined according to modified NCEP/ATP III criteria. Multivariable regression analysis accounting for competing risks was performed using a modified Cox proportional hazard model in order to assess the association between diabetes, the MS and the subsequent development of prostate cancer. RESULTS: At baseline, subjects were classified into one of the four groups: (1) 6119 (53%) with neither diabetic mellitus nor MS, (2) 3376 (29%) with the MS but without diabetes, (3) 560 (5%) with diabetes mellitus but without MS and (4) 1486 (13%) with both conditions. Median follow-up was 12.7 years (range 0-15.7 years). During follow-up, 459 new cases of prostate cancer were recorded. The age-adjusted hazard ratio (HR) for prostate cancer was reduced in diabetic patients compared with those without diabetes, 0.54 and 95% confidence interval of 0.40-0.73. No significant association was noted between the presence of MS and prostate cancer development. On multivariate analysis, diabetes mellitus continued to protect against the development of prostate cancer, this was more pronounced in the absence of MS (HR=0.43, P=0.01 for diabetes in the absence of MS; HR=0.64, P=0.08 in the presence of MS). CONCLUSIONS: The results of this study indicate an inverse association between type 2 diabetes mellitus and prostate cancer risk.

Early toxicity predicts long-term survival in high-grade glioma.

BACKGROUND: Patients with high-grade gliomas are treated with surgery followed by chemoradiation. The risk factors and implications of neurological side effects are not known. METHODS: Acute and late ≥ grade 3 neurological toxicities (NTs) were analysed among 2761 patients from 14 RTOG trials accrued from 1983 to 2003. The association between acute and late toxicity was analysed using a stepwise logistic regression model. The association between the occurrence of acute NT and survival was analysed as an independent variable. RESULTS: There were 2610 analysable patients (86% glioblastoma, 10% anaplastic astrocytoma). All received a systemic agent during radiation (83% chemotherapy, 17% biological agents). Median radiation dose was 60 Gy. There were 182 acute and 83 late NT events. On univariate analysis, older age, poor performance status, aggressive surgery, pre-existing neurological dysfunction, poor mental status and twice-daily radiation were associated with increased acute NT. In a stepwise logistic regression model the occurrence of acute NT was significantly associated with late NT (OR=2.40; 95% CI=1.2-4.8; P=0.014). The occurrence of acute NT predicted poorer overall survival, independent of recursive partitioning analysis class (median 7.8 vs 11.8 months). INTERPRETATION: Acute NT is significantly associated with both late NT and overall survival.

Extreme leukocytosis in the emergency department.

BACKGROUND: Extreme leukocytosis in the absence of haematological disease, is a topic about which little is known, although it may be associated with increased mortality among patients admitted to the intensive care department. The significance of extreme leukocytosis in patients presenting to hospital is uncertain. AIM: To study the correlates and prognostic significance of extreme leukocytosis, in patients admitted to an emergency department. DESIGN: Observational study. METHODS: Consecutive adult patients with extreme leukocytosis (>25 x 10(9)/l, n=54) presenting to the emergency department of a university-affiliated hospital were compared to age-matched controls (+/-5 years) with moderate leukocytosis (12-25 x 10(9)/l, n=118) presenting to the same department. Data were collected on demographic features, emergency room findings and hospital course. RESULTS: Patients with extreme leukocytosis were more likely to suffer from infectious disease (74% vs. 48%, p<0.01), to be hospitalized (100% vs. 80%, p<0.001), and to die (32.1% vs. 12.7%, p<0.01), and had a longer median length of stay (7.5 vs. 4.0 days, p<0.005). There was no significant difference in vital signs between the two groups. DISCUSSION: In our patients, extreme leukocytosis appeared to be predominantly caused by infectious disease, and was associated with a high case fatality rate. The degree of leukocytosis may provide prognostic information beyond that reflected in traditional vital signs.