Prostate cancer radiotherapy: potential applications of metal nanoparticles for imaging and therapy

Prostate cancer (CaP) is the most commonly diagnosed cancer in males. There have been dramatic technical advances in radiotherapy delivery, enabling higher doses of radiotherapy to primary cancer, involved lymph nodes and oligometastases with acceptable normal tissue toxicity. Despite this, many patients relapse following primary radical therapy, and novel treatment approaches are required. Metal nanoparticles are agents that promise to improve diagnostic imaging and image-guided radiotherapy and to selectively enhance radiotherapy effectiveness in CaP. We summarize current radiotherapy treatment approaches for CaP and consider pre-clinical and clinical evidence for metal nanoparticles in this condition.

Prostate cancer (CaP) is the most commonly diagnosed cancer in males and is responsible for more than 10,000 deaths each year in the UK.1 Technical advances in radiotherapy delivery, including image-guided intensity-modulated radiotherapy (IG-IMRT), have enabled the delivery of higher radiation dose to the prostate, which has led to improved biochemical control. Further improvements in cancer imaging during radiotherapy are being developed with the advent of MRI simulators and MRI linear accelerators.2–4

Nanotechnology promises to deliver significant advancements across numerous disciplines.5 The widest scope of applications are from the biomedical field including exogenous gene/drug delivery systems, advanced biosensors, targeted contrast agents for diagnostic applications and as direct therapeutic agents used in combination with existing treatment modalities.6–11 This diversity of application is especially evident within cancer research, with a myriad of experimental anticancer strategies currently under investigation.

This review will focus specifically on the potential of metal-based nanoparticles to augment the efficacy of radiotherapy in CaP, a disease where radiotherapy constitutes a major curative treatment modality.12 Furthermore, we will also address the clinical state of the art for CaP radiotherapy and consider how these treatments could be best combined with nanotherapeutics to improve cancer outcomes.

Quantification of the smoking-associated cancer risk with rate advancement periods: meta-analysis of individual participant data from cohorts of the CHANCES consortium

BACKGROUND: Smoking is the most important individual risk factor for many cancer sites but its association with breast and prostate cancer is not entirely clear. Rate advancement periods (RAPs) may enhance communication of smoking related risk to the general population. Thus, we estimated RAPs for the association of smoking exposure (smoking status, time since smoking cessation, smoking intensity, and duration) with total and site-specific (lung, breast, colorectal, prostate, gastric, head and neck, and pancreatic) cancer incidence and mortality.

METHODS: This is a meta-analysis of 19 population-based prospective cohort studies with individual participant data for 897,021 European and American adults. For each cohort we calculated hazard ratios (HRs) for the association of smoking exposure with cancer outcomes using Cox regression adjusted for a common set of the most important potential confounding variables. RAPs (in years) were calculated as the ratio of the logarithms of the HRs for a given smoking exposure variable and age. Meta-analyses were employed to summarize cohort-specific HRs and RAPs.

RESULTS: Overall, 140,205 subjects had a first incident cancer, and 53,164 died from cancer, during an average follow-up of 12 years. Current smoking advanced the overall risk of developing and dying from cancer by eight and ten years, respectively, compared with never smokers. The greatest advancements in cancer risk and mortality were seen for lung cancer and the least for breast cancer. Smoking cessation was statistically significantly associated with delays in the risk of cancer development and mortality compared with continued smoking.

CONCLUSIONS: This investigation shows that smoking, even among older adults, considerably advances, and cessation delays, the risk of developing and dying from cancer. These findings may be helpful in more effectively communicating the harmful effects of smoking and the beneficial effect of smoking cessation.

The relationship between body mass index and breast cancer recurrence/progression and breast cancer-specific death

The aim of this study was to describe the nonlinear association between body mass index (BMI) and breast cancer outcomes and to determine whether BMI improves prediction of outcomes. A cohort of906 breast cancer patients diagnosed at Henry Ford Health System, Detroit (1985-1990) were studied. The median follow-up was 10 years. Multivariate logistic regression was used to model breast cancer recurrence/progression and breast cancer-specific death. Restricted cubic splines were used to model nonlinear effects. Receiver operator characteristic areas under the curves (ROC AUC) were used to evaluate prediction. BMI was nonlinearly associated with recurrence/progression and death (p= 0.0230 and 0.0101). Probability of outcomes increased with increase or decrease ofBMI away from 25. BMI splines were suggestive of improved prediction of death. The ROC AUCs for nested models with and without BMI were 0.8424 and 0.8331 (p= 0.08). I f causally associated, modifying patients BMI towards 25 may improve outcomes.

Exemestane Versus Anastrozole in Postmenopausal Women With Early Breast Cancer: NCIC CTG MA.27—A Randomized Controlled Phase III Trial

PURPOSE In patients with hormone-dependent postmenopausal breast cancer, standard adjuvant therapy involves 5 years of the nonsteroidal aromatase inhibitors anastrozole and letrozole. The steroidal inhibitor exemestane is partially non-cross-resistant with nonsteroidal aromatase inhibitors and is a mild androgen and could prove superior to anastrozole regarding efficacy and toxicity, specifically with less bone loss. PATIENTS AND METHODS We designed an open-label, randomized, phase III trial of 5 years of exemestane versus anastrozole with a two-sided test of superiority to detect a 2.4% improvement with exemestane in 5-year event-free survival (EFS). Secondary objectives included assessment of overall survival, distant disease-free survival, incidence of contralateral new primary breast cancer, and safety. RESULTS In the study, 7,576 women (median age, 64.1 years) were enrolled. At median follow-up of 4.1 years, 4-year EFS was 91% for exemestane and 91.2% for anastrozole (stratified hazard ratio, 1.02; 95% CI, 0.87 to 1.18; P = .85). Overall, distant disease-free survival and disease-specific survival were also similar. In all, 31.6% of patients discontinued treatment as a result of adverse effects, concomitant disease, or study refusal. Osteoporosis/osteopenia, hypertriglyceridemia, vaginal bleeding, and hypercholesterolemia were less frequent on exemestane, whereas mild liver function abnormalities and rare episodes of atrial fibrillation were less frequent on anastrozole. Vasomotor and musculoskeletal symptoms were similar between arms. CONCLUSION This first comparison of steroidal and nonsteroidal classes of aromatase inhibitors showed neither to be superior in terms of breast cancer outcomes as 5-year initial adjuvant therapy for postmenopausal breast cancer by two-way test. Less toxicity on bone is compatible with one hypothesis behind MA.27 but requires confirmation. Exemestane should be considered another option as up-front adjuvant therapy for postmenopausal hormone receptor-positive breast cancer.

Trends in Treatment Patterns and Outcomes for Ductal Carcinoma In Situ

BACKGROUND Impact of contemporary treatment of pre-invasive breast cancer (ductal carcinoma in situ [DCIS]) on long-term outcomes remains poorly defined. We aimed to evaluate national treatment trends for DCIS and to determine their impact on disease-specific (DSS) and overall survival (OS). METHODS The Surveillance, Epidemiology, and End Results (SEER) registry was queried for patients diagnosed with DCIS from 1991 to 2010. Treatment pattern trends were analyzed using Cochran-Armitage trend test. Survival analyses were performed using inverse probability weights (IPW)-adjusted competing risk analyses for DSS and Cox proportional hazard regression for OS. All tests performed were two-sided. RESULTS One hundred twenty-one thousand and eighty DCIS patients were identified. The greatest proportion of patients was treated with lumpectomy and radiation therapy (43.0%), followed by lumpectomy alone (26.5%) and unilateral (23.8%) or bilateral mastectomy (4.5%) with significant shifts over time. The rate of sentinel lymph node biopsy increased from 9.7% to 67.1% for mastectomy and from 1.4% to 17.8% for lumpectomy. Compared with mastectomy, OS was higher for lumpectomy with radiation (hazard ratio [HR] = 0.79, 95% confidence interval [CI] = 0.76 to 0.83, P < .001) and lower for lumpectomy alone (HR = 1.17, 95% CI = 1.13 to 1.23, P < .001). IPW-adjusted ten-year DSS was highest in lumpectomy with XRT (98.9%), followed by mastectomy (98.5%), and lumpectomy alone (98.4%). CONCLUSIONS We identified substantial shifts in treatment patterns for DCIS from 1991 to 2010. When outcomes between locoregional treatment options were compared, we observed greater differences in OS than DSS, likely reflecting both a prevailing patient selection bias as well as clinically negligible differences in breast cancer outcomes between groups.

Shifting the focus: Addressing breast cancer disparities at the health care organization level

The purpose of this study was to understand the scope of breast cancer disparities within the Texas Medical Center. The goal was to increase the awareness of breast cancer disparities at the health care organization level, and to foster the development of organizational interventions to reduce breast cancer disparities. The study seeks to answer the following questions: 1. Are hospitals in the Texas Medical Center implementing interventions to reduce breast cancer disparities? 2. What are their interventions for reducing the effects of non clinical factors on breast cancer treatment disparities? 3. What are their measures for monitoring, continuously improving, and evaluating the success of their interventions? ^ This research project was designed as a mixed methods case study. Quantitative breast cancer data for the years 2000-2009 was obtained from the Texas Cancer Registry (TCR). Qualitative data collection and analysis was done by conducting a total of 20 semi-structured interviews of administrators, physicians and nurses at five hospitals (A, B, C, D and E) in the Texas Medical Center (TMC). For quantitative analysis, the study was limited to early stage breast cancer patients: local and regional. The dependent variable was receipt of standard treatment: Surgery (Yes/No), BCS vs Mastectomy, Chemotherapy (Yes/No) and Radiation after BCS (Yes/No). The main independent variable was race: non-Hispanic White (NHW) , non-Hispanic Black (NHB), and Hispanic. Other covariates included age at diagnosis, diagnosis date, percent poverty, grade, stage, and regional nodes. Multivariate logistic regression was used to test the adjusted association between receipt of standard care and race. Qualitative data was analyzed with the Atlas.ti7 software (ATLAS.ti GmbH, Berlin). ^ Though there were significant differences by race for all dependent variables when the data was analyzed as a single group of all hospitals; at the level of the individual hospitals the results were not consistent by race/ethnicity across all dependent variables for hospitals A, B, and E. There were no racial differences in adjusted analysis for receipt of chemotherapy for the individual hospitals of interest in this study. For hospitals C and D, no racial disparities in treatment was observed in adjusted multivariable analysis. All organizations in this study were aware of the body of research which shows that there are disparities in breast cancer outcomes for patient population groups. However, qualitative data analysis found that there were differences in interest among hospitals in addressing breast cancer disparities in their patient population groups. Some organizations were actively implementing directed measures to reduce the breast cancer disparity gap in outcomes for patients, and others were not. Despite the differences in levels of interest, quantitative data analysis showed that organizations in the Texas Medical Center were making progress in reducing the burden of breast cancer disparities in the patient populations being served.^

Ambient Air Pollution and Lung Cancer Risk in the Women's Health Initiative Observational Study

Thesis (Master's)--University of Washington, 2016-06

Shooting for the Moon or Flying Too Near the Sun? Crossing the Value Rubicon in Precision Cancer Care

In his last two State of the Union addresses, President Barack Obama has focused on the need to deliver innovative solutions to improve human health, through the Precision Medicine Initiative in 2015 and the recently announced Cancer Moonshot in 2016. Precision cancer care has delivered clear patient benefit, but even for high-impact medicines such as imatinib mesylate (Glivec) in chronic myeloid leukaemia, the excitement at the success of this practice-changing clinical intervention has been somewhat tempered by the escalating price of this 'poster child' for precision cancer medicine (PCM). Recent studies on the costs of cancer drugs have revealed significant price differentials, which are a major causative factor behind disparities in the access to new generations of immunological and molecularly targeted agents. In this perspective, we will discuss the benefits of PCM to modern cancer control, but also emphasise how increasing costs are rendering the current approaches to integrating the paradigm of PCM unsustainable. Despite the ever increasing pressure on cancer and health care budgets, innovation will and must continue. Value-based frameworks offer one of the most rational approaches for policymakers committed to improving cancer outcomes through a public health approach.

A Qualitative Assessment of Breast Cancer Advocates in Bolivia, Colombia, Ecuador and Peru

Thesis (Master's)--University of Washington, 2016-06

Risk of Malignant Progression in Barrett’s Esophagus Patients: Results from a Large Population-Based Study

Background: Barrett's esophagus (BE) is a premalignant lesion that predisposes to esophageal adenocarcinoma. However, the reported incidence of esophageal adenocarcinoma in patients with BE varies widely. We examined the risk of malignant progression in patients with BE using data from the Northern Ireland Barrett's esophagus Register (NIBR), one of the largest population-based registries of BE worldwide, which includes every adult diagnosed with BE in Northern Ireland between 1993 and 2005.

Subjects and Methods: We followed 8522 patients with BE, defined as columnar lined epithelium of the esophagus with or without specialized intestinal metaplasia (SIM), until the end of 2008. Patients with incident adenocarcinomas of the esophagus or gastric cardia or with high-grade dysplasia of the esophagus were identified by matching the NIBR with the Northern Ireland Cancer Registry, and deaths were identified by matching with records from the Registrar General's Office. Incidence of cancer outcomes or high-grade dysplasia was calculated as events per 100 person-years (% per year) of follow-up, and Cox proportional hazard models were used to determine incidence by age, sex, length of BE segment, presence of SIM, macroscopic BE, or low-grade dysplasia. All P values were from two-sided tests.

Results: After a mean of 7.0 years of follow-up, 79 patients were diagnosed with esophageal cancer, 16 with cancer of the gastric cardia, and 36 with high-grade dysplasia. In the entire cohort, incidence of esophageal or gastric cardia cancer or high-grade dysplasia combined was 0.22% per year (95% confidence interval [CI] = 0.19% to 0.26%). SIM was found in 46.0% of patients. In patients with SIM, the combined incidence was 0.38% per year (95% CI = 0.31 to 0.46%). The risk of cancer was statistically significantly elevated in patients with vs without SIM at index biopsy (0.38% per year vs 0.07% per year; hazard ratio [HR] = 3.54, 95% CI = 2.09 to 6.00, P <. 001), in men compared with women (0.28% per year vs 0.13% per year; HR = 2.11, 95% CI = 1.41 to 3.16, P <. 001), and in patients with low-grade dysplasia compared with no dysplasia (1.40% per year vs 0.17% per year; HR = 5.67, 95% CI = 3.77 to 8.53, P <. 001).

Conclusion: We found the risk of malignant progression among patients with BE to be lower than previously reported, suggesting that currently recommended surveillance strategies may not be cost-effective. © The Author 2011. Published by Oxford University Press. All rights reserved.

Age-specific risk factor profiles of adenocarcinomas of the esophagus: a pooled analysis from the international BEACON consortium

Esophageal (EA) and esophagogastric junction (EGJA) adenocarcinoma have been steadily increasing in frequency in younger people, however the etiology of these cancers is poorly understood. We therefore investigated associations of body- mass index (BMI), cigarette smoking, alcohol consumption, gastroesophageal reflux, and use of non-steroidal anti-inflammatory drugs (NSAIDs) in relation to age-specific risks of EA and EGJA. We pooled individual participant data from eight population-based, case-control studies within the international Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON). The analysis included 1,363 EA patients, 1,472 EGJA patients, and 5,728 control participants. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for age-specific (<50, 50–59, 60–69, ≥70 years) cancer outcomes, as well as interactions by age. BMI, smoking status and pack-years, recurrent gastroesophageal reflux, and frequency of gastroesophageal reflux were positively associated with EA and EGJA in each age group. Early-onset EA (<50 years) had stronger associations with recurrent gastroesophageal reflux (OR=8.06, 95%CI: 4.52, 14.37; Peffect modification=0.01) and BMI (ORBMI ≥30 vs. <25=4.19, 95%CI: 2.23, 7.87; Peffect modification=0.04), relative to older age groups. In contrast, inverse associations of NSAID use were strongest in the oldest age group (≥70 years), although this apparent difference was not statistically significant. Age-specific associations with EGJA showed similar, but slightly weaker patterns and no statistically significant differences by age were observed. Our study provides evidence that associations between obesity and gastroesophageal reflux are stronger among earlier onset EA cancers.