Nanoparticle technology: future opportunities in cancer treatment

Gold nanoparticles are emerging as promising agents for cancer therapy and are being investigated as vehicles for drug delivery, agents for photothermal therapy, image contrast and radiosensitisation. This review introduces the field of nanotechnology with a focus on recent gold nanoparticle research which has led to early phase clinical trials. In particular the increasing preclinical evidence for gold nanoparticles as sensitizers with ionizing radiation in vitro and in vivo is discussed.

Non-pharmacological interventions for cognitive impairment due to systemic cancer treatment (Review)

Background

It is estimated that up to 75% of cancer survivors may experience cognitive impairment as a result of cancer treatment and given the increasing size of the cancer survivor population, the number of affected people is set to rise considerably in coming years. There is a need, therefore, to identify effective, non-pharmacological interventions for maintaining cognitive function or ameliorating cognitive impairment among people with a previous cancer diagnosis.
Objectives

To evaluate the cognitive effects, non-cognitive effects, duration and safety of non-pharmacological interventions among cancer patients targeted at maintaining cognitive function or ameliorating cognitive impairment as a result of cancer or receipt of systemic cancer treatment (i.e. chemotherapy or hormonal therapies in isolation or combination with other treatments).
Search methods

We searched the Cochrane Centre Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PUBMED, Cumulative Index of Nursing and Allied Health Literature (CINAHL) and PsycINFO databases. We also searched registries of ongoing trials and grey literature including theses, dissertations and conference proceedings. Searches were conducted for articles published from 1980 to 29 September 2015.
Selection criteria

Randomised controlled trials (RCTs) of non-pharmacological interventions to improve cognitive impairment or to maintain cognitive functioning among survivors of adult-onset cancers who have completed systemic cancer therapy (in isolation or combination with other treatments) were eligible. Studies among individuals continuing to receive hormonal therapy were included. We excluded interventions targeted at cancer survivors with central nervous system (CNS) tumours or metastases, non-melanoma skin cancer or those who had received cranial radiation or, were from nursing or care home settings. Language restrictions were not applied.
Data collection and analysis

Author pairs independently screened, selected, extracted data and rated the risk of bias of studies. We were unable to conduct planned meta-analyses due to heterogeneity in the type of interventions and outcomes, with the exception of compensatory strategy training interventions for which we pooled data for mental and physical well-being outcomes. We report a narrative synthesis of intervention effectiveness for other outcomes.
Main results

Five RCTs describing six interventions (comprising a total of 235 participants) met the eligibility criteria for the review. Two trials of computer-assisted cognitive training interventions (n = 100), two of compensatory strategy training interventions (n = 95), one of meditation (n = 47) and one of physical activity intervention (n = 19) were identified. Each study focused on breast cancer survivors. All five studies were rated as having a high risk of bias. Data for our primary outcome of interest, cognitive function were not amenable to being pooled statistically. Cognitive training demonstrated beneficial effects on objectively assessed cognitive function (including processing speed, executive functions, cognitive flexibility, language, delayed- and immediate- memory), subjectively reported cognitive function and mental well-being. Compensatory strategy training demonstrated improvements on objectively assessed delayed-, immediate- and verbal-memory, self-reported cognitive function and spiritual quality of life (QoL). The meta-analyses of two RCTs (95 participants) did not show a beneficial effect from compensatory strategy training on physical well-being immediately (standardised mean difference (SMD) 0.12, 95% confidence interval (CI) -0.59 to 0.83; I2= 67%) or two months post-intervention (SMD - 0.21, 95% CI -0.89 to 0.47; I2 = 63%) or on mental well-being two months post-intervention (SMD -0.38, 95% CI -1.10 to 0.34; I2 = 67%). Lower mental well-being immediately post-intervention appeared to be observed in patients who received compensatory strategy training compared to wait-list controls (SMD -0.57, 95% CI -0.98 to -0.16; I2 = 0%). We assessed the assembled studies using GRADE for physical and mental health outcomes and this evidence was rated to be low quality and, therefore findings should be interpreted with caution. Evidence for physical activity and meditation interventions on cognitive outcomes is unclear.
Authors' conclusions

Overall, the, albeit low-quality evidence may be interpreted to suggest that non-pharmacological interventions may have the potential to reduce the risk of, or ameliorate, cognitive impairment following systemic cancer treatment. Larger, multi-site studies including an appropriate, active attentional control group, as well as consideration of functional outcomes (e.g. activities of daily living) are required in order to come to firmer conclusions about the benefits or otherwise of this intervention approach. There is also a need to conduct research into cognitive impairment among cancer patient groups other than women with breast cancer.

Breast cancer mortality in neighbouring European countries with different level of breast screening but similar access to treatment: An analysis of WHO mortality database

Objective: To compare trends in breast cancer mortality within three pairs of neighbouring European countries in relation to implementation of screening. Design: Retrospective trend analysis.
Setting: Three country pairs (Northern Ireland (United Kingdom) v Republic of Ireland, the Netherlands v Belgium and Flanders (Belgian region south of the Netherlands), and Sweden v Norway).
Data sources: WHO mortality database on cause of death and data sources on mammography screening, cancer treatment, and risk factors for breast cancer mortality.
Main outcome measures: Changes in breast cancer mortality calculated from linear regressions of log transformed, age adjusted death rates. Joinpoint analysis was used to identify the year when trends in mortality for all ages began to change.
Results: From 1989 to 2006, deaths from breast cancer decreased by 29% in Northern Ireland and by 26% in the Republic of Ireland; by 25% in the Netherlands and by 20% in Belgium and 25% in Flanders; and by 16% in Sweden and by 24% in Norway. The time trend and year of downward inflexion were similar between Northern Ireland and the Republic of Ireland and between the Netherlands and Flanders. In Sweden, mortality rates have steadily decreased since 1972, with no downward inflexion until 2006. Countries of each pair had similar healthcare services and prevalence of risk factors for breast cancer mortality but differing implementation of mammography screening, with a gap of about 10-15 years.
Conclusions: The contrast between the time differences in implementation of mammography screening and the similarity in reductions in mortality between the country pairs suggest that screening did not play a direct part in the reductions in breast cancer mortality.

Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial

Background: When cure is impossible, cancer treatment should focus on both length and quality of life. Maximisation of time without toxic effects could be one effective strategy to achieve both of these goals. The COIN trial assessed preplanned treatment holidays in advanced colorectal cancer to achieve this aim. Methods: COIN was a randomised controlled trial in patients with previously untreated advanced colorectal cancer. Patients received either continuous oxaliplatin and fluoropyrimidine combination (arm A), continuous chemotherapy plus cetuximab (arm B), or intermittent (arm C) chemotherapy. In arms A and B, treatment continued until development of progressive disease, cumulative toxic effects, or the patient chose to stop. In arm C, patients who had not progressed at their 12-week scan started a chemotherapy-free interval until evidence of disease progression, when the same treatment was restarted. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and B is described in a companion paper. Here, we compare arms A and C, with the primary objective of establishing whether overall survival on intermittent therapy was non-inferior to that on continuous therapy, with a predefined non-inferiority boundary of 1·162. Intention-to-treat (ITT) and per-protocol analyses were done. This trial is registered, ISRCTN27286448. Findings: 1630 patients were randomly assigned to treatment groups (815 to continuous and 815 to intermittent therapy). Median survival in the ITT population (n=815 in both groups) was 15·8 months (IQR 9·4—26·1) in arm A and 14·4 months (8·0—24·7) in arm C (hazard ratio [HR] 1·084, 80% CI 1·008—1·165). In the per-protocol population (arm A, n=467; arm C, n=511), median survival was 19·6 months (13·0—28·1) in arm A and 18·0 months (12·1—29·3) in arm C (HR 1·087, 0·986—1·198). The upper limits of CIs for HRs in both analyses were greater than the predefined non-inferiority boundary. Preplanned subgroup analyses in the per-protocol population showed that a raised baseline platelet count, defined as 400 000 per µL or higher (271 [28%] of 978 patients), was associated with poor survival with intermittent chemotherapy: the HR for comparison of arm C and arm A in patients with a normal platelet count was 0·96 (95% CI 0·80—1·15, p=0·66), versus 1·54 (1·17—2·03, p=0·0018) in patients with a raised platelet count (p=0·0027 for interaction). In the per-protocol population, more patients on continuous than on intermittent treatment had grade 3 or worse haematological toxic effects (72 [15%] vs 60 [12%]), whereas nausea and vomiting were more common on intermittent treatment (11 [2%] vs 43 [8%]). Grade 3 or worse peripheral neuropathy (126 [27%] vs 25 [5%]) and hand—foot syndrome (21 [4%] vs 15 [3%]) were more frequent on continuous than on intermittent treatment. Interpretation: Although this trial did not show non-inferiority of intermittent compared with continuous chemotherapy for advanced colorectal cancer in terms of overall survival, chemotherapy-free intervals remain a treatment option for some patients with advanced colorectal cancer, offering reduced time on chemotherapy, reduced cumulative toxic effects, and improved quality of life. Subgroup analyses suggest that patients with normal baseline platelet counts could gain the benefits of intermittent chemotherapy without detriment in survival, whereas those with raised baseline platelet counts have impaired survival and quality of life with intermittent chemotherapy and should not receive a treatment break.

The regulation and role of osteopontin in malignant transformation and cancer.

Osteopontin (OPN) is a predominantly secreted extracellular matrix glycophosphoprotein which binds to alpha v-containing integrins and has an important role in malignant cell attachment and invasion. High OPN expression in the primary tumor is associated with early metastasis and poor outcome in human breast and other cancers. Forced OPN overexpression in benign cells may induce neoplastic-like cell behaviour including increased attachment and invasion in vitro as well as the ability to metastasize in vivo. Conversely, OPN inhibition by antisense cDNA impedes cell growth and tumor forming capacity. OPN is not mutationally activated in cancer but its expression is regulated by Wnt/Tcf signaling, steroid receptors, growth factors, ras, Ets and AP-1 transcription factors. Presumably these factors are implicated in induction of OPN overexpression in cancer. Greater understanding of the role of OPN in neoplastic change and its transcriptional regulation may enable development of novel cancer treatment strategies

Availability of complementary and alternative medicine for people with cancer in the British National Health Service: Results of a national survey

This study assessed access to Complementary and Alternative Medicine (CAM) therapies for people with cancer within the British National Health Service. CAM units were identified through an internet search in 2009. A total of 142 units, providing 62 different therapies, were identified: 105 (74.0%) England; 23 (16.2%) Scotland; 7 (4.9%) each in Wales and Northern Ireland. Most units provide a small number of therapies (median 4, range 1–20), and focus on complementary, rather than alternative approaches. Counselling is the most widely provided therapy (available at 82.4% of identified units), followed by reflexology (62.0%), aromatherapy (59.1%), reiki (43.0%), massage (42.2%). CAM units per million of the population varied between countries (England: 2.2; Wales: 2.3; Scotland: 4.8; Northern Ireland: 5.0), and within countries. Better publicity for CAM units, greater integration of units in conventional cancer treatment centres may help improve access to CAMs.

A randomized controlled trial of a self-management psychosocial intervention for men with prostate cancer and their partners: a study protocol.

Background
Little is known about interventions to help men and their partners cope with the after effects of prostate cancer treatment. The lack of in-depth descriptions of the intervention content is hindering the identification of which intervention (or component of an intervention) works.

Aim
To describe the development and evaluation of the content of a self-management psychosocial intervention for men with prostate cancer and their partners.

Design
A feasibility randomized controlled trial including structure, process, and outcome analysis.

Methods
This 9-week intervention commences on completion of treatment and consists of three group and two telephone sessions. The intervention focuses on symptom management, sexual dysfunction, uncertainty management, positive thinking and couple communication. Forty-eight couples will be assigned to either the intervention or a control group receiving usual care. Participants will be assessed at baseline, immediately postintervention and at 1 and 6 months postintervention. Outcome measures for patients and caregivers include self-efficacy, quality of life, symptom distress, uncertainty, benefits of illness, health behaviour, and measures of couple communication and support. An additional caregiver assessment will be completed by the partner.

Discussion
The main purpose of this feasibility study is to investigate the acceptability of the CONNECT programme to men with prostate cancer and their partners and to gain feedback from the participants and facilitators to make changes to and enhance the programme. Reasons why men do not want to participate will be collated to enhance recruitment in the future. We will also test recruitment strategies, randomization procedures, and the acceptability of the questionnaires. Ethical approval granted December 2010.

BRCA1--conductor of the breast stem cell orchestra:the role of BRCA1 in mammary gland development and identification of cell of origin of BRCA1 mutant breast cancer

Breast cancer treatment has been increasingly successful over the last 20 years due in large part to targeted therapies directed against different subtypes. However, basal-like breast cancers still represent a considerable challenge to clinicians and scientists alike since the pathogenesis underlying the disease and the target cell for transformation of this subtype is still undetermined. The considerable similarities between basal-like and BRCA1 mutant breast cancers led to the hypothesis that these cancers arise from transformation of a basal cell within the normal breast epithelium through BRCA1 dysfunction. Recently, however, a number of studies have called this hypothesis into question. This review summarises the initial findings which implicated the basal cell as the cell of origin of BRCA1 related basal-like breast cancers, as well as the more recent data which identifies the luminal progenitor cells as the likely target of transformation. We compare a number of key studies in this area and identify the differences that could explain some of the contradictory findings. In addition, we highlight the role of BRCA1 in breast cell differentiation and lineage determination by reviewing recent findings in the field and our own observations suggesting a role for BRCA1 in stem cell regulation through activation of the p63 and Notch pathways. We hope that through an increased understanding of the BRCA1 role in breast differentiation and the identification of the cell(s) of origin we can improve treatment options for both BRCA1 mutant and basal-like breast cancer subgroups.

Multidimensional rehabilitation programmes for adult cancer survivors

Background: Multidimensional rehabilitation programmes (MDRPs) have developed in response to the growing number of people living with and surviving cancer. MDRPs comprise a physical component and a psychosocial component. Studies of the effectiveness of these programmes have not been reviewed and synthesised.

Objectives: To conduct a systematic review of studies examining the effectiveness of MDRPs in terms of maintaining or improving the physical and psychosocial well-being of adult cancer survivors.

Search methods: We conducted electronic searches in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL and PsychINFO up to February 2012.

Selection criteria: Selection criteria focused on randomised controlled trials (RCTs) of multidimensional interventions for adult cancer survivors. Interventions had to include a physical component and a psychosocial component and to have been carried out on two or more occasions following completion of primary cancer treatment. Outcomes had to be assessed using validated measures of physical health and psychosocial well-being. Non-English language papers were included.

Data collection and analysis: Pairs of review authors independently selected trials, rated their methodological quality and extracted relevant data. Although meta-analyses of primary and secondary endpoints were planned there was a high level of study heterogeneity and only one common outcome measure (SF-36) could be statistically synthesised. In addition, we conducted a narrative analysis of interventions, particularly in terms of inspecting and identifying intervention components, grouping or categorising interventions and examining potential common links and outcomes.

Main results: Twelve RCTs (comprising 1669 participants) met the eligibility criteria. We judged five studies to have a moderate risk of bias and assessed the remaining seven as having a high risk of bias. It was possible to include SF-36 physical health component scores from five studies in a meta-analysis. Participating in a MDRP was associated with an increase in SF-36 physical health component scores (mean difference (MD) 2.22, 95% confidence interval (CI) 0.12 to 4.31, P = 0.04). The findings from the narrative analysis suggested that MDRPs with a single domain or outcome focus appeared to be more successful than programmes with multiple aims. In addition, programmes that comprised participants with different types of cancer compared to cancer site-specific programmes were more likely to show positive improvements in physical outcomes. The most effective mode of service delivery appeared to be face-to-face contact supplemented with at least one follow-up telephone call. There was no evidence to indicate that MDRPs which lasted longer than six months improved outcomes beyond the level attained at six months. In addition, there was no evidence to suggest that services were more effective if they were delivered by a particular type of health professional.

Authors' conclusions: There is some evidence to support the effectiveness of brief, focused MDRPs for cancer survivors. Rigorous and methodologically sound clinical trials that include an economic analysis are required.

Clinical potential of gene-directed enzyme prodrug therapy to improve radiation therapy in prostate cancer patients

Despite the advances in prostate cancer diagnosis and treatment, current therapies are not curative in a significant proportion of patients. Gene-directed enzyme prodrug therapy (GDEPT), when combined with radiation therapy, could improve the outcome of treatment for prostate cancer, the second leading cause of cancer death in the western world. GDEPT involves the introduction of a therapeutic transgene, which can be targeted to the tumour cells. A prodrug is administered systemically and is converted to its toxic form only in those cells containing the transgene, resulting in cell kill. This review will discuss the clinical trials which have investigated the potential of GDEPT at various stages of prostate cancer progression. The advantages of using GDEPT in combination with radiotherapy will be examined, as well as some of the recent advances which enhance the potential utility of GDEPT.

Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce apoptosis in multi-drug-resistant cancer cells

PURPOSE: The development of multi-drug resistance (MDR) due to the expression of members of the ATP binding cassette (ABC) transporter family is a major obstacle in cancer treatment. The broad range of substrate specificities associated with these transporters leads to the efflux of many anti-cancer drugs from tumour cells. Therefore, the development of new chemotherapeutic agents that are not substrates of these transporters is important. We have recently demonstrated that some members of a novel series of pyrrolo-1,5-benzoxazepine (PBOX) compounds are microtubule-depolymerising agents that potently induce apoptosis in several cancer cell lines and impair growth of mouse breast tumours. The aim of this current study was to establish whether PBOXs were capable of inducing apoptosis in cancer cells expressing either P-glycoprotein or breast cancer resistance protein (BCRP), two of the main ABC transporters associated with MDR.

METHODS: We performed in vitro studies to assess the effects of PBOXs on cell proliferation, cell cycle and apoptosis in human cancer cell lines and their drug-resistant substrains expressing either P-glycoprotein or BCRP. In addition, we performed a preliminary molecular docking study to examine interactions between PBOXs and P-glycoprotein.

RESULTS: We established that three representative PBOXs, PBOX-6, -15 and -16 were capable of inducing apoptosis in drug-resistant HL60-MDR1 cells (expressing P-glycoprotein) and HL60-ABCG2 cells (expressing BCRP) with similar potencies as in parental human promyelocytic leukaemia HL60 cells. Likewise, resistance to PBOX-6 and -16 was not evident in P-glycoprotein-expressing A2780-ADR cells in comparison with parent human ovarian carcinoma A2780 cells. Finally, we deduced by molecular docking that PBOX-6 is not likely to form favourable interactions with the substrate binding site of P-glycoprotein.

CONCLUSION: Our results suggest that pro-apoptotic PBOX compounds may be potential candidates for the treatment of P-glycoprotein- or BCRP-associated MDR cancers.

Hypoxia in prostate cancer:a powerful shield against tumour destruction?

Tumour hypoxia is progressively emerging as a common feature of prostate tumours associated with poor prognosis. While the molecular basis of disease progression is increasingly well documented, the potential role of hypoxia in these processes remains poorly evaluated. By dissecting the impact of hypoxia-inducible factor 1 alpha on molecular responses, this review provides evidence for a powerful protecting role of oxygen deprivation against oxidative stress injury, androgen deprivation, chemotherapeutic and radiation cytotoxicity. We propose hypoxia as a potent tumour-induced shield against destruction and suggest its targeting may need to be routinely addressed in the management of prostate cancer.