Loss in life expectancy and gain in life years as measures of cancer impact

There are a broad range of survival-based metrics that are available to report from cancer survival studies, with varying advantages and disadvantages. A combination of metrics should be considered to improve comprehensibility and give a fuller understanding of the impact of cancer. In this article, we discuss the utility of loss in life expectancy and gain in life years as measures of cancer impact, and to quantify differences across population groups. These measures are simple to interpret, have a real-world meaning, and evaluate impact over a life-time horizon. We illustrate the use of the loss in life expectancy measures through a range of examples using data on women diagnosed with cancer in England. We use four different examples across a number of tumour types to illustrate different uses of the metrics, and highlight how they can be interpreted and used in practice in population-based oncology studies. Extensions of the measures conditional on survival to specific times after diagnosis can be used to give updated prognosis for cancer patients. Furthermore, we show how the measures can be used to understand the impact of population differences seen across patient groups. We believe that these under-used, and relatively easy to calculate, measures of overall impact can supplement reporting of cancer survival metrics and improve the comprehensibility compared to the metrics typically reported.     

Life expectancy change in perturbed communities: derivation and qualitative analysis

Pollution, loss of habitat, and climate change are introducing dramatic perturbations to natural communities and affecting public health. Populations in perturbed communities can change dynamically, in both abundance and age structure. While analysis of the community matrix can predict changes in population abundance arising from a sustained or press perturbation, perturbations also have the potential to modify life expectancy, which adds yet another means to falsify experimental hypotheses and to monitor management interventions in natural systems. In some instances, an input to a community will produce no change in the abundance of a population but create a major shift in its mean age. We present an analysis of change in both abundance and life expectancy, leading to a formal quantitative assessment as well as qualitative predictions, and illustrate the usefulness of the technique through general examples relating to vector-borne disease and fisheries.     

Adiponectin as a growth inhibitor in prostate cancer cells

Prostate cancer is associated with obesity. However, the molecular basis of this association is not well known. Adiponectin is a major adipose cytokine that decreases in circulation in obesity and ameliorates obesity. Here, we identify adiponectin as a novel inhibitor in prostate cancer cell growth. Adiponectin occurs in non-proteolytic (full-length adiponectin: f-adiponectin) and proteolytic (globular adiponectin) forms in various oligomeric states (trimer, hexamer, and high molecular weight complex). The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay demonstrates that f-adiponectin inhibits prostate cancer cell growth drastically at subphysiological concentrations. Furthermore, velocity sedimentation analysis shows that the high molecular weight complex of f-adiponectin is the inhibitory form. Moreover, f-adiponectin suppresses leptin- and/or insulin-like growth factor-I (IGF-I)-stimulated, androgen-independent DU145 cell growth, and dihydrotestosterone-stimulated, androgen-dependent LNCaP-FGC cell growth. In addition, f-adiponectin enhances doxorubicin inhibition of prostate cancer cell growth. Therefore, f-adiponectin is a molecular mediator between prostate cancer and obesity, and may be therapeutic to prostate cancer.     

The use of PSA as biomarker in nutritional intervention studies of prostate cancer

Epidemiological evidence suggests that environmental factors, such as diet, play a role in the development and progression of prostate cancer (PC). The number of potential protective dietary compounds or whole dietary products that are indicated to have preventive effects is piling up and demands further evaluation. The number of options urges for a reliable high-throughput screening system. To face this growing field, we suggest a strategy that combines prostate-specific antigen (PSA)-based clinical trials with experimental human xenograft studies to evaluate potential chemopreventive agents for PC. This review describes the first results that have come available using this method. In Rotterdam, two nutrition-based tertiary chemoprevention trials were conducted in patients aiming to delay progression of minimal PC. In these studies two different supplements were used both consisting of a (different) mixture of components reported to be related to cancer prevention. PC patients that were locally treated but had rising levels of circulating PSA of unknown origin were randomised into a double-blind, placebo-controlled study with a crossover design. PSA kinetics was followed during the two intervention periods. The time frame of the study design was 6 months. Results of these intervention studies showed increased PSA doubling times after dietary supplementation as compared to placebo. The lack of information on tumor burden in these patients requires the need for additional xenograft studies that can provide supplement-induced PSA and tumor responses. Such parallel experimental studies will enable to validate PSA as a biomarker for tumor volume response and may link clinical PSA kinetics to actual tumor response. For one of the clinical study, such an experimental confirmation study was performed. The dietary supplement similar to what was used in the clinical study was administered to animals that were injected intraprostatically with human PC-346C cells. Responses on tumor growth and PSA were recorded over time and allowed to monitor a potential differential effect on PSA or tumor growth. This animal study revealed no difference in response as determined by tumor volume or PSA release between supplemented and placebo mice, and confirmed that PSA levels reflected tumor response under this specific dietary intervention. We propose that the strategy of PSA-based early phase II clinical trials accompanied by experimental human xenograft studies, to assess the reliability of PSA response to reflect tumor response, allows for a concise, relatively fast test system that is able to screen the various treatment options for chemoprevention in a relatively short period of time.     

The androgen receptor: a potential target for therapy of prostate cancer

The androgen receptor plays a pivotal role in the prostate. Its primary function is to provide responsive gene products for differentiation and growth, but under abnormal conditions it contributes to the development of prostate cancer. The goal of this review is to elucidate the molecular functions of the androgen receptor and its role in prostate cancer. Initially the function of the androgen receptor will be described. Next, the clinical diagnosis, epidemiological impact, and treatments of androgen-dependent and -independent prostate cancer will be discussed. Finally we will examine how the mechanism of androgen action has played a role in the translation of new therapies and how this may influence future treatment modalities of prostate cancer.     

Hsp90: Still a viable target in prostate cancer

Heat shock protein 90 (Hsp90) is a molecular chaperone that regulates the maturation, activation and stability of critical signaling proteins that drive the development and progression of prostate cancer, including the androgen receptor. Despite robust preclinical data demonstrating anti-tumor activity of first-generation Hsp90 inhibitors in prostate cancer, poor clinical responses initially cast doubt over the clinical utility of this class of agent. Recent advances in compound design and development, use of novel preclinical models and further biological insights into Hsp90 structure and function have now stimulated a resurgence in enthusiasm for these drugs as a therapeutic option. This review highlights how the development of new-generation Hsp90 inhibitors with improved physical and pharmacological properties is unfolding, and discusses the potential contexts for their use either as single agents or in combination, for men with metastatic prostate cancer.     

Optimization of diarylpentadienones as chemotherapeutics for prostate cancer

Our earlier studies indicate that (1E,4E)-1,5-bis(1-alkyl-1H-imidazol-2-yl)penta-1,4-diene-3-ones and (1E,4E)-1,5-bis(1-alkyl-1H-benzo[d]imidazol-2-yl)penta-1,4-diene-3-ones exhibit up to 121-fold greater antiproliferative potency than curcumin in human prostate cancer cell models, but only 2–10 fold increase in mouse plasma concentrations. The present study aims to further optimize them as anti-prostate cancer agents with both good potency and bioavailability. (1E,4E)-1,5-Bis(1H-imidazol-2-yl)penta-1,4-diene-3-one, the potential metabolic product of (1E,4E)-1,5-bis(1-alkyl-1H-imidazol-2-yl)penta-1,4-diene-3-ones, was synthesized and evaluated for its anti-proliferative activity. The promising potency of 1,5-bis(1-alkyl-1H-imidazol-2-yl)penta-1,4-diene-3-ones was completely abolished by removing the 1-alkyl group, suggesting the critical role of an appropriate group on the N1 position. We then envisioned that N-aryl substitution to exclude the C–H bond on the carbon adjacent to the N1 position (α-H) may increase the metabolic stability. Consequently, seven (1E,4E)-1,5-bis(1-aryl-1H-imidazol-2-yl)penta-1,4-dien-3-ones and three (1E,4E)-1,5-bis(1-aryl-1H-benzo[d]imidazol-2-yl)penta-1,4-dien-3-ones, as well as three (1E,4E)-1,5-bis(1-aryl-1H-pyrrolo[3,2-b]pyridine-2-yl)penta-1,4-dien-3-ones, were synthesized through a three-step transformation, including N-arylation via Ullmann condensation, formylation, and Horner-Wadsworth-Emmons reaction. Six optimal (1E,4E)-1,5-bis(1-aryl-1H-imidazol-2-yl)penta-1,4-dien-3-ones exhibit 24- to 375-fold improved potency as compared with curcumin. Replacement of the imidazole with bulkier benzoimidazole and 4-azaindole results in a substantial decrease in the potency. (1E,4E)-1,5-Bis(1-(2-methoxyphenyl)-1H-imidazol-2-yl)penta-1,4-dien-3-one (17d) was established as an optimal compound with both superior potency and good bioavailability that is sufficient to provide the therapeutic efficacy necessary to suppress in vivo tumor growth.     

The life expectancy of phlebotomine sandflies: first field estimates from southern France

Abstract. 1. A field study of Phlebotomus ariasi Tonnoir, the vector of Leishmania infantum Nicolle in southern France, addressed the following questions: Is it possible to estimate reliably the life expectancy of this sandfly; can spatial or temporal variation in the life expectancy be detected, and is such variation significant for disease transmission? 2. Life expectancy was estimated by examining follicular relics in the ovaries of more than ten thousand females caught in light traps at seven sites in the Cévennes and the Garrigues, throughout their active period in 1985 and 1986. Whilst the distinction between nulliparous and parous flies was easily made, assessments of the number of times a parous fly had laid eggs were unreliable. Best estimates of life expectancy were therefore calculated from the parous rate. 3. Large samples collected from one site in the Cevennes in both years gave very similar estimates of life expectancy. 4. There was also no significant difference between estimates obtained from the Cévennes and the Garrigues, despite their distinct vegetation and climates. Therefore, large regional differences in sandfly population size and the prevalence of canine leishmaniasis cannot be explained by a difference in adult survival rate. 5. With no systematic annual or regional variation, a useful mean life expectancy can be calculated from the data collected at all sites in both years. It is 1.54 (SE 0.04) ovarian cycles. However, this estimate is sensitive to the assumption that survival rate is a discrete rather than a continuous variable. 6. Local variation in the parous rate may be associated with the proximity of traps to P.ariasi emergence sites.     

The role of medical physics in prostate cancer radiation therapy

Medical physics, both as a scientific discipline and clinical service, hugely contributed and still contributes to the advances in the radiotherapy of prostate cancer. The traditional translational role in developing and safely implementing new technology and methods for better optimizing, delivering and monitoring the treatment is rapidly expanding to include new fields such as quantitative morphological and functional imaging and the possibility of individually predicting outcome and toxicity. The pivotal position of medical physicists in treatment personalization probably represents the main challenge of current and next years and needs a gradual change of vision and training, without losing the traditional and fundamental role of physicists to guarantee a high quality of the treatment. The current focus issue is intended to cover traditional and new fields of investigation in prostate cancer radiation therapy with the aim to provide up-to-date reference material to medical physicists daily working to cure prostate cancer patients. The papers presented in this focus issue touch upon present and upcoming challenges that need to be met in order to further advance prostate cancer radiation therapy. We suggest that there is a smart future for medical physicists willing to perform research and innovate, while they continue to provide high-quality clinical service. However, physicists are increasingly expected to actively integrate their implicitly translational, flexible and high-level skills within multi-disciplinary teams including many clinical figures (first of all radiation oncologists) as well as scientists from other disciplines.     

Metformin and statins: a possible role in high-risk prostate cancer

Aim and backgroundThere is increasing evidence that statins and oral anti-diabetic drugs, such as metformin, can have a favorable role in advanced prostate cancer treatment.Metformin has been shown to inhibit proliferation of tumor cells in vitro and statins inhibit carcinogenesis by suppressing angiogenesis/invasion mechanisms. However, clinical evidence on the protective effect of these drugs is still weak.The purpose of this study is to analyze if these drugs have an impact on Biochemical-Failure-Free-Survival (BFFS) and on Distant-Failure-Free-Survival (DFFS) in localized high-risk prostate cancer.Material and MethodsFrom 2002–2016, 447 patients with histologically confirmed high-risk prostate cancer were retrospectively evaluated. All patients received radiotherapy and androgen deprivation therapy. Biochemical recurrence was determined by the Phoenix criteria and metastatic patients were defined by the presence of radiological metastasis. Survival analysis was performed using the Kaplan-Meier method.Results175 patients were treated with statins (65.3 % with a dose ≤ 20 mg/day) and 70 with metformin (75.7 % with a dose ≤ 1700 mg/day). Median follow-up was 88 months (1–194) with no differences in BFFS and DFFS between metformin and non-metformin patients (77.4 % versus 80 %, p = 0.91 and 89.4 % versus 88.7 %, p = 0.56, respectively). We did not find a statistical difference in BFFS and DFFS in patients taking higher doses of those drugs.ConclusionMetformin and statins were not associated with BFFS or DFFS improvement in our analysis. However, the small number of patients treated with these drugs limits the reliability of the results and prospective studies are needed.     

Proton beam and prostate cancer: An evolving debate

This paper evaluates the reasons behind the rise in the use of proton beam for prostate cancer, the economics drivers behind it, and the evidence that exists to support it. It concludes that clinical outcome data underlying the notion that this is a superior treatment remains sparse and discusses what is needed to fill in the gaps.     

2H-1,2,3-Triazole-chalcones as novel cytotoxic agents against prostate cancer

Prostate cancer is an important cause of death in the male population and for which there is no satisfactory chemotherapy. Herein a new series of chalcone hybrids containing 2H-1,2,3-triazole core as the ring B has been synthesized and evaluated in vitro against PC-3 prostate cancer cell line. Compounds 4a, 4c and 4e significantly reduced cell viability and showed IC₅₀ of 28.55, 15.64 and 25.56 µM, respectively. The structure-activity relationship supported by computational chemistry points that the polarity of the molecular surface area should have some relevance to the efficiency of the compounds, in particular the ratio of the partial positive charge sites and the total molecular surface area exposed to the cell environment.     

The fat side of prostate cancer

Prostate cancer (PCa) metabolism appears to be unique in comparison with other types of solid cancers. Normal prostate cells mainly rely on glucose oxidation to provide precursors for the synthesis and secretion of citrate, resulting in an incomplete Krebs cycle and minimal oxidative phosphorylation for energy production. In contrast, during transformation, PCa cells no longer secrete citrate and they reactivate the Krebs cycle as energy source. Moreover, primary PCas do not show increased aerobic glycolysis and therefore they are not efficiently detectable with ¹⁸F-FDG-PET. However, increased de novo lipid synthesis, strictly intertwined with deregulation in classical oncogenes and oncosuppressors, is an early event of the disease. Up-regulation and increased activity of lipogenic enzymes (including fatty acid synthase and choline kinase) occurs throughout PCa carcinogenesis and correlates with worse prognosis and poor survival. Thus, lipid precursors such as acetate and choline have been successfully used as alternative tracers for PET imaging. Lipid synthesis intermediates and FA catabolism also emerged as important players in PCa maintenance. Finally, epidemiologic studies suggested that systemic metabolic disorders including obesity, metabolic syndrome, and diabetes as well as hypercaloric and fat-rich diets might increase the risk of PCa. However, how metabolic disorders contribute to PCa development and whether dietary lipids and de novo lipids synthesized intra-tumor are differentially metabolized still remains unclear. In this review, we examine the switch in lipid metabolism supporting the development and progression of PCa and we discuss how we can exploit its lipogenic nature for therapeutic and diagnostic purposes. This article is part of a Special Issue entitled Lipid Metabolism in Cancer.     

Long-term survival of patients with prostate cancer in Martinique: Results of a population-based study

BackgroundMartinique has one of the highest incidences of prostate cancer (PCa) worldwide. We analysed overall survival (OS) among patients with PCa in Martinique, using data from a population-based cancer registry between 2005 and 2014.MethodsThe log-rank test was used to assess the statistical differences between survival curves according to age at diagnosis, risk of disease progression including Gleason score, stage at diagnosis and Prostate Specific Antigen (PSA). A multivariable Cox model was constructed to identify independent prognostic factors for OS.ResultsA total of 5045 patients were included with a mean age at diagnosis of 68.1±9.0 years [36.0 – 98.0 years]. Clinical stage was analysed in 4999 (99.1% of overall), 19.5% were at low risk, 34.7% intermediate and 36.9% at high risk. In our study, 8.9% of patients with available stage at diagnosis, were regional/metastatic cancers. Median PSA level at diagnosis was 10.4 ng/mL. High-risk PCa was more frequent in patients aged 65-74 and ≥75 years as compared to those aged <65 years (36.6% and 48.8% versus 28.7% respectively; p<0.0001). One-year OS was 96.3%, 5-year OS was 83.4 and 10-year OS was 65.0%. Median survival was not reached in the whole cohort. High-risk PCa (HR=2.32; p<0.0001), regional/metastatic stage (HR= 9.51; p<0.0001) and older age (65-74 and ≥75 years - respectively HR=1.70; and HR=3.38), were independent prognostic factors for OS (p<0.0001).ConclusionThis study provides long term data that may be useful in making cancer management decisions for patients with PCa in Martinique.     

Estimated life expectancy and risk of death from cancer by quartiles in the older Japanese population: 2010 vital statistics

Data on life expectancies and risk of death from cancer are essential information to have when making informed decisions about cancer screening and treatment options, but has never been presented in a way that is readily available to use for physicians in Japan. We provided estimates of life expectancies and predicted risk of death from seven most common types of cancer (lung, gastric, liver, colon, prostate, breast, and cervical) by quartiles for the older Japanese population above 50 years old, using 2010 life tables and cancer mortality statistics data. We found that there was a large difference in life expectancy between older persons in the upper and lower quartiles. Risk of death from breast cancer was low. By using this data, physicians can more accurately obtain life expectancy estimates by assessing which quartile the patient is most likely to fall under, and help patients make better informed decisions.     

The synthesis of neurotensin antagonist SR 48692 for prostate cancer research

An improved synthesis of the molecule SR 48692 is presented and its use as a neurotensin antagonist biological probe for use in cancer research is described. The preparation includes an number of enhanced chemical conversions and strategies to overcome some of the limiting synthetic transformations in the original chemical route.     

Implementation of intensity modulated radiotherapy for prostate cancer in a private radiotherapy service in Mexico

Intensity modulated radiation therapy (IMRT) allows physicians to deliver higher conformal doses to the tumour, while avoiding adjacent structures. As a result the probability of tumour control is higher and toxicity may be reduced. However, implementation of IMRT is highly complex and requires a rigorous quality assurance (QA) program both before and during treatment. The present article describes the process of implementing IMRT for localized prostate cancer in a radiation therapy department. In our experience, IMRT implementation requires careful planning due to the need to simultaneously implement specialized software, multifaceted QA programs, and training of the multidisciplinary team. Establishing standardized protocols and ensuring close collaboration between a multidisciplinary team is challenging but essential.     

Small-molecule androgen receptor downregulators as an approach to treatment of advanced prostate cancer

Chemical starting points were investigated for downregulation of the androgen receptor as an approach to treatment of advanced prostate cancer. Although prototypic steroidal downregulators such as 6a designed for intramuscular administration showed insufficient cellular potency, a medicinal chemistry program derived from a novel androgen receptor ligand 8a led to 6-[4-(4-cyanobenzyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (10b), for which high plasma levels following oral administration in a preclinical model compensate for moderate cellular potency.     

Life expectancy of oil palm (Elaeis guineensis) infected by Ganoderma boninense in coastal soils,Malaysia: a case study

Ganoderma boninense basal stem rot poses a serious threat to the oil palm industry. The effects of external disease symptoms and coastal soils (Briah – Typic Endoaquepts, Jawa – Typic Sulfaquepts, and Selangor – Typic Humaquepts) on the life expectancy of the infected palms, from disease detection to death, were studied. Six-monthly censuses on disease classes for each palm were recorded between 2004 and 2012. Survival curves of disease symptoms and soil types were compared using Kaplan–Meier and log-rank methods, respectively. Ganoderma-infected palms in acid-sulphate (AS) and potential AS soils recorded lower life expectancy. Survival duration of infected palms with foliar symptoms was 12-months shorter. External factors, such as soil type may influence the survival of infected palms and soil types may pre-dispose oil palm to higher risk of Ganoderma infection. More effective Ganoderma management for palms planted on Coastal soils (with and without AS layer) have been proposed.