Cancer stem cell targeted therapy: progress amid controversies

Although cancer stem cells have been well characterized in numerous malignancies, the fundamental characteristics of this group of cells, however, have been challenged by some recent observations: cancer stem cells may not necessary to be rare within tumors; cancer stem cells and non-cancer stem cells may undergo reversible phenotypic changes; and the cancer stem cells phenotype can vary substantially between patients. Here the current status and progresses of cancer stem cells theory is illustrated and via providing a panoramic view of cancer therapy, we addressed the recent controversies regarding the feasibility of cancer stem cells targeted anti-cancer therapy.

Exercise for health : a breast cancer recovery program - quality of life benefits [Conference Abstract]

Introduction: Five-year survival from breast cancer in Australia is 87%. Hence, ensuring a good quality of life (QOL) has become a focal point of cancer research and clinical interest. Exercise during and after treatment has been identified as a potential strategy to optimise QOL of women diagnosed with breast cancer.----- Methods: Exercise for Health is a randomised controlled trial of an eight-month, exercise intervention delivered by Exercise Physiologists. An objective of this study was to assess the impact of the exercise program during and following treatment on QOL. Queensland women diagnosed with unilateral breast cancer in 2006/07 were eligible to participate. Those living in urban-Brisbane (n=194) were allocated to either the face-to-face exercise group, the telephone exercise group, or the usual-care group, and those living in rural Queensland (n=143) were allocated to the telephone exercise group or the usual-care group. QOL, as assessed by the Functional Assessment of Cancer Therapy-Breast (FACT-B+4) questionnaire, was measured at 4-6 weeks (pre-intervention), 6 months (mid-intervention) and 12 months (three months post-intervention) post-surgery.----- Results: Significant (P<0.01) increases in QOL were observed between pre-intervention and three months post-intervention 12 months post-surgery for all women. Women in the exercise groups experienced greater mean positive changes in QOL during this time (+10 points) compared with the usual-care groups (+5 to +7 points) after adjusting for baseline QOL. Although all groups experienced an overall increase in QOL, approximately 20% of urban and rural women in the usual-care groups reported a decline in QOL, compared with 10% of women in the exercise groups.----- Conclusions: This work highlights the potential importance of participating in physical activity to optimise QOL following a diagnosis of breast cancer. Results suggest that the telephone may be an effective medium for delivering exercise counselling to newly diagnosed breast cancer patients.

The prognostic significance of quality of life following breast cancer [Conference Abstract]

Introduction: Evidence suggests a positive association between quality of life (QOL). and overall survival(OS). among metastatic breast cancer (BC). patients, although the relationship in early-stage BC is unclear. This work examines the association between QOL and OS following a diagnosis of early-stage BC. ----- Methods: A population-based sample of Queensland women (n=287). with early-stage, invasive, unilateral BC, were prospectively observed for a median of 6.6 years. QOL was assessed at six and 18 months post-diagnosis using the Functional Assessment of Cancer Therapy, Breast FACT-B+4. questionnaire. Raw scores for the FACT-B+4 scales were computed and individuals were categorised according to whether QOL declined, remained stable or improved over time. OS was measured from the date of diagnosis to the date of death or was censored at the date of last follow-up. Risk ratios (RR) and 95% confidence intervals (CI). for the association between QOL and OS were obtained using Cox proportional hazards survival models adjusted for confounding characteristics. ----- Results: A total of 27 (9.4%). women died during the follow-up period. Three baseline QOL scales (emotional, general and overall QOL) were significantly associated with OS, with RRs ranging between 0.89 95% CI: 0.81, 0.98; P=0.01. and 0.98 (95% CI: 0.96, 0.99; P=0.03),indicating a 2%-11% reduced risk of death for every one unit increase in QOL. When QOL was categorised according to changes between six and 18 months post-diagnosis, analyses showed that for those who experienced declines in functional and physical QOL, risk of death increased by two- (95% CI: 1.43, 12.52; P<0.01) and four-fold (95% CI: 1.15, 7.19; P=0.02), respectively. Conclusions: This work indicates that specific QOL scales at six months post-diagnosis, and changes in certain QOL scales over the subsequent 12-month period (as measured by the FACT-B+4), are associated with overall survival in women with early-stage breast cancer.

What determines the health-related quality of life among regional and rural breast cancer survivors?

Objective: To assess the health-related quality of life (HRQoL) of regional and rural breast cancer survivors at 12 months post-diagnosis and to identify correlates of HRQoL. Methods: 323 (202 regional and 121 rural) Queensland women diagnosed with unilateral breast cancer in 2006/2007 participated in a population-based, cross-sectional study. HRQoL was measured using the Functional Assessment of Cancer Therapy, Breast plus arm morbidity (FACT-B+4) self-administered questionnaire. Results: In age-adjusted analyses, mean HRQoL scores of regional breast cancer survivors were comparable to their rural counterparts 12 months post-diagnosis (122.9, 95% CI: 119.8, 126.0 vs. 123.7, 95% CI: 119.7, 127.8; p>0.05). Irrespective of residence, younger (<50 years) women reported lower HRQoL than older (50+ years) women (113.5, 95% CI: 109.3, 117.8 vs. 128.2, 95%CI: 125.1, 131.2; p<0.05). Those women who received chemotherapy, reported two complications post-surgery, had poorer upper-body function than most, reported more stress, reduced coping, who were socially isolated, had no confidante for social-emotional support, had unmet healthcare needs, and low health self-efficacy reported lower HRQoL scores. Together, these factors explained 66% of the variance in overall HRQoL. The pattern of results remained similar for younger and older age groups. Conclusions and Implications: The results underscore the importance of supporting and promoting regional and rural breast cancer programs that are designed to improve physical functioning, reduce stress and provide psychosocial support following diagnosis. Further, the information can be used by general practitioners and other allied health professionals for identifying women at risk of poorer HRQoL.

Age-related differences in exercise and quality of life among breast cancer survivors

Purpose: Physical activity has become a focus of cancer recovery research as it has the potential to reduce treatment-related burden and optimize health-related quality of life (HRQoL). However, the potential for physical activity to influence recovery may be age-dependent. This paper describes physical activity levels and HRQoL among younger and older women after surgery for breast cancer and explores the correlates of physical inactivity. Methods: A population-based sample of breast cancer patients diagnosed in South-East Queensland, Australia, (n=287) were assessed once every three months, from 6 to 18 months post-surgery. The Functional Assessment of Cancer Therapy-Breast questionnaire (FACTB+4) and items from the Behavioral Risk Factor Surveillance System (BRFSS) questionnaire were used to measure HRQoL and physical activity, respectively. Physical activity was assigned metabolic equivalent task (MET) values, and categorized as < 3, 3 to 17.9 and 18+ MET-hours/weeks. Descriptive statistics, generalized linear models with age stratification (<50 years versus 50+ years), and logistic regression were used for analyses (p=0.05, two-tailed). Results: Younger women who engaged in 3 or more MET-hours/week of physical activity reported a higher HRQoL at 18 months compared to their more sedentary counterparts (p<0.05). Older women reported similar HRQoL irrespective of activity level and consistently reported clinically higher HRQoL than younger women. Increasing age, being overweight or obese, and restricting use of the treated side at six months post-surgery increased the likelihood of sedentary behavior (OR>3, p<0.05). Conclusions: Age influences the potential to observe HRQoL benefits related to physical activity participation. These results also provide relevant information for the design of exercise interventions for breast cancer survivors and highlights that some groups of women are at greater risk of long-term sedentary behavior.

Depression, anxiety and body image after treatment for invasive stage one epithelial ovarian cancer

Background: Diagnosis of epithelial ovarian cancer (EOC) in young women has major implications including those to their reproductive potential. We evaluated depression, anxiety and body image in patients with stage I EOC treated with fertility sparing surgery (FSS) or radical surgery (RS). We also investigated fertility outcomes after FSS.----- Methods: A retrospective study was undertaken in which 62 patients completed questionnaires related to anxiety, depression, body image and fertility outcomes. Additional information on adjuvant therapy after FSS and RS and demographic details were abstracted from medical records. Both bi and multivariate regression models were used to assess the relationship between demographic, clinical and pathological results and scores for anxiety, depression and body image.----- Results: Thirty-nine patients underwent RS and the rest, FSS. The percentage of patients reporting elevated anxiety and depression (subscores ≥ 11) were 27 % and 5% respectively. The median (inter quartile range) score for body image scale (BIS) was 6 (3-15). None of the demographic or clinical factors examined showed significant association with anxiety and BIS with the exception of ‘time since diagnosis’. For depression, post-menopausal status was the only independent predictor. Among those 23 patients treated by FSS, 14 patients tried to conceive (7 successful), resulting in 7 live births, one termination of pregnancy and one miscarriage.----- Conclusion: This study shows that psychological issues are common in women treated for stage I EOC. Reproduction after FSS is feasible and lead to the birth of healthy babies in about half of patients who wished to have another child. Further prospective studies with standardised instruments are required.

Does quality of life among breast cancer survivors one year after diagnosis differ depending on urban and non-urban residence? A comparative study

Background: This study examined the quality of life (QOL), measured by the Functional Assessment of Cancer Therapy (FACT) questionnaire, among urban (n=277) and non-urban (n=323) breast cancer survivors and women from the general population (n=1140) in Queensland, Australia. ---------- Methods: Population-based samples of breast cancer survivors aged <75 years who were 12 months post-diagnosis and similarly-aged women from the general population were recruited between 2002 and 2007. ---------- Results: Age-adjusted QOL among urban and non-urban breast cancer survivors was similar, although QOL related to breast cancer concerns was the weakest domain and was lower among non-urban survivors than their urban counterparts (36.8 versus 40.4, P<0.01). Irrespective of residence, breast cancer survivors, on average, reported comparable scores on most QOL scales as their general population peers, although physical well-being was significantly lower among non-urban survivors (versus the general population, P<0.01). Overall, around 20%-33% of survivors experienced lower QOL than peers without the disease. The odds of reporting QOL below normative levels were increased more than two-fold for those who experienced complications following surgery, reported upper-body problems, had higher perceived stress levels and/or a poor perception of handling stress (P<0.01 for all). ---------- Conclusions: Results can be used to identify subgroups of women at risk of low QOL and to inform components of tailored recovery interventions to optimize QOL for these women following cancer treatment.

Patterns, correlates, and prognostic significance of quality of life following breast cancer

Objective To describe quality of life (QOL) over a 12-month period among women with breast cancer, consider the association between QOL and overall survival (OS), and explore characteristics associated with QOL declines. Methods A population-based sample of Australian women (n=287) with invasive, unilateral breast cancer (Stage I+), was observed prospectively for a median of 6.6 years. QOL was assessed at six, 12 and 18 months post-diagnosis, using the Functional Assessment of Cancer Therapy, Breast (FACT-B+4) questionnaire. Raw scores for the FACT-B+4 and subscales were computed and individuals were categorized according to whether QOL declined, remained stable or improved between six and 18 months. Kaplan-Meier and Cox proportional hazards survival methods were used to estimate OS and its associations with QOL. Logistic regression models identified factors associated with QOL decline. Results Within FACT-B+4 sub-scales, between 10% and 23% of women showed declines in QOL. Following adjustment for established prognostic factors, emotional wellbeing and FACT-B+4 scores at six months post-diagnosis were associated with OS (p<0.05). Declines in physical (p<0.01) or functional (p=0.02) well-being between six and 18 months post-diagnosis were also associated significantly with OS. Receiving multiple forms of adjuvant treatment, a perception of not handling stress well and reporting one or more other major life events at six months post-diagnosis were factors associated with declines in QOL in multivariable analyses. Conclusions Interventions targeted at preventing QOL declines may ultimately improve quantity as well as quality of life following breast cancer.

Pretreatment malnutrition and quality of life - association with prolonged length of hospital stay among patients with gynecological cancer: A cohort study

Background Length of hospital stay (LOS) is a surrogate marker for patients' well-being during hospital treatment and is associated with health care costs. Identifying pretreatment factors associated with LOS in surgical patients may enable early intervention in order to reduce postoperative LOS. Methods This cohort study enrolled 157 patients with suspected or proven gynecological cancer at a tertiary cancer centre (2004-2006). Before commencing treatment, the scored Patient Generated - Subjective Global Assessment (PG-SGA) measuring nutritional status and the Functional Assessment of Cancer Therapy-General (FACT-G) scale measuring quality of life (QOL) were completed. Clinical and demographic patient characteristics were prospectively obtained. Patients were grouped into those with prolonged LOS if their hospital stay was greater than the median LOS and those with average or below average LOS. Results Patients' mean age was 58 years (SD 14 years). Preoperatively, 81 (52%) patients presented with suspected benign disease/pelvic mass, 23 (15%) with suspected advanced ovarian cancer, 36 (23%) patients with suspected endometrial and 17 (11%) with cervical cancer, respectively. In univariate models prolonged LOS was associated with low serum albumin or hemoglobin, malnutrition (PG-SGA score and PG-SGA group B or C), low pretreatment FACT-G score, and suspected diagnosis of cancer. In multivariable models, PG-SGA group B or C, FACT-G score and suspected diagnosis of advanced ovarian cancer independently predicted LOS. Conclusions Malnutrition, low quality of life scores and being diagnosed with advanced ovarian cancer are the major determinants of prolonged LOS amongst gynecological cancer patients. Interventions addressing malnutrition and poor QOL may decrease LOS in gynecological cancer patients.

Quality of life after total laparoscopic hysterectomy versus total abdominal hysterectomy for stage I endometrial cancer (LACE) : a randomised trial

Background: The two-stage Total Laparoscopic Hysterectomy (TLH) versus Total Abdominal Hysterectomy (TAH) for stage I endometrial cancer (LACE) randomised controlled trial was initiated in 2005. The primary objective of stage 1 was to assess whether TLH results in equivalent or improved QoL up to 6 months after surgery compared to TAH. The primary objective of stage 2 was to test the hypothesis that disease-free survival at 4.5 years is equivalent for TLH and TAH. Results addressing the primary objective of stage 1 of the LACE trial are presented here. Methods: The first 361 LACE participants (TAH n= 142, TLH n=190) were enrolled in the QoL substudy at 19 centres across Australia, New Zealand and Hong Kong, and 332 completed the QoL analysis. Randomisation was performed centrally and independently from other study procedures via a computer generated, web-based system (providing concealment of the next assigned treatment) using stratified permuted blocks of 3 and 6, and assigned patients with histologically confirmed stage 1 endometrioid endometrial adenocarcinoma and ECOG performance status <2 to TLH or TAH stratified by histological grade and study centre. No blinding of patients or study personnel was attempted. QoL was measured at baseline, 1 and 4 weeks (early), and 3 and 6 months (late) after surgery using the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire. The primary endpoint was the difference between the groups in QoL change from baseline at early and late time points (a 5% difference was considered clinically significant). Analysis was performed according to the intention-to-treat principle using generalized estimating equations on differences from baseline for the early and late QoL recovery. The LACE trial is registered with clinicaltrials.gov (NCT00096408) and the Australian New Zealand Clinical Trials Registry (CTRN12606000261516). Patients for both stages of the trial have now been recruited and are being followed up for disease-specific outcomes. Findings: The proportion of missing values at the 5%, 10% 15% and 20% differences in the FACT-G scale was 6% (12/190) in the TLH and 14% (20/142) in the TAH group. There were 8/332 conversions (2.4%, 7 of which were from TLH to TAH). In the early phase of recovery, patients undergoing TLH reported significantly greater improvement of QoL from baseline compared to TAH in all subscales except the emotional and social well-being subscales. Improvements in QoL up to 6 months post-surgery continued to favour TLH except for the emotional and social well-being of the FACT and the visual analogue scale of the EuroQoL five dimensions (EuroQoL-VAS). Length of operating time was significantly longer in the TLH group (138±43 mins), than in the TAH group at (109±34 mins; p=0.001). While the proportion of intraoperative adverse events was similar between the treatment groups (TAH 8/142, 5.6%; TLH 14/190, 7.4%; p=0.55), postoperatively, twice as many patients in the TAH group experienced adverse events of CTC grade 3+ than in the TLH group (33/142, 23.2% and 22/190, 11.6%, respectively; p=0.004). Postoperative serious adverse events occurred more frequently in patients who had a TAH (27/142, 19.0%) than a TLH (15/190, 7.9%) (p=0.002). Interpretation: QoL improvements from baseline during early and later phases of recovery, and the adverse event profile significantly favour TLH compared to TAH for patients treated for Stage I endometrial cancer.

Upper-body morbidity following breast cancer treatment is common, may persist longer-term and adversely influences quality of life

Background: Impairments in upper-body function (UBF) are common following breast cancer. However, the relationship between arm morbidity and quality of life (QoL) remains unclear. This investigation uses longitudinal data to describe UBF in a population-based sample of women with breast cancer and examines its relationship with QoL. ---------- Methods: Australian women (n = 287) with unilateral breast cancer were assessed at three-monthly intervals, from six- to 18-months post-surgery (PS). Strength, endurance and flexibility were used to assess objective UBF, while the Disability of the Arm, Shoulder and Hand questionnaire and the Functional Assessment of Cancer Therapy- Breast questionnaire were used to assess self-reported UBF and QoL, respectively. ---------- Results: Although mean UBF improved over time, up to 41% of women revealed declines in UBF between sixand 18-months PS. Older age, lower socioeconomic position, treatment on the dominant side, mastectomy, more extensive lymph node removal and having lymphoedema each increased odds of declines in UBF by at least twofold (p < 0.05). Lower baseline and declines in perceived UBF between six- and 18-months PS were each associated with poorer QoL at 18-months PS (p < 0.05). ---------- Conclusions: Significant upper-body morbidity is experienced by many following breast cancer treatment, persisting longer term, and adversely influencing the QoL of breast cancer survivors.

Challenging the distal-to-proximal cannulation technique for administration of anti-cancer therapies : a prospective cohort study

Background: Distal-to-proximal technique has been recommended for anti-cancer therapy administration. There is no evidence to suggest that a 24-hour delay of treatment is necessary for patients with a previous uncomplicated venous puncture proximal to the administration site. Objectives: This study aims to identify if the practice of 24-hour delay between a venous puncture and subsequent cannulation for anti-cancer therapies at a distal site is necessary for preventing extravasation. Methods: A prospective cohort study was conducted with 72 outpatients receiving anti-cancer therapy via an administration site distal to at least one previous uncomplicated venous puncture on the same arm in a tertiary cancer centre in Australia. Participants were interviewed and assessed at baseline data before treatment and on day 7 for incidence of extravasation/phlebitis. Results: Of 72 participants with 99 occasions of treatment, there was one incident of infiltration (possible extravasation) at the venous puncture site proximal to the administration site and two incidents of phlebitis at the administration site. Conclusions: A 24 hour delay is unnecessary if an alternative vein can be accessed for anti-cancer therapy after a proximal venous puncture. Implications for practice: Extravasation can occur at a venous puncture site proximal to an administration site in the same vein. However, the nurse can administer anti-cancer therapy at a distal site if the nurse can confidently determine the vein of choice is not in any way connected to the previous puncture site through visual inspection and palpation.

Safety, feasibility and effects of an individualised walking intervention for women undergoing chemotherapy for ovarian cancer : a pilot study

Background: Exercise interventions during adjuvant cancer therapy have been shown to increase functional capacity, relieve fatigue and distress and may assist rates of chemotherapy completion. These studies have been limited to breast, gastric and mixed cancer groups and it is not yet known if a similar intervention is even feasible among women with ovarian cancer. We aimed to assess safety, feasibility and potential effect of a walking intervention in women undergoing chemotherapy for ovarian cancer. Methods: Women newly diagnosed with ovarian cancer were recruited to participate in an individualised walking intervention throughout chemotherapy and were assessed pre-and post-intervention. Feasibility measures included session adherence, compliance with exercise physiologist prescribed walking targets and self-reported program acceptability. Changes in objective physical functioning (6 minute walk test), self-reported distress (Hospital Anxiety and Depression Scale), symptoms (Memorial Symptom Assessment Scale - Physical) and quality of life (Functional Assessment of Cancer Therapy - Ovarian) were calculated, and chemotherapy completion and adverse intervention effects recorded. Results: Seventeen women were enrolled (63% recruitment rate). Mean age was 60 years (SD = 8 years), 88% were diagnosed with FIGO stage III or IV disease, 14 women underwent adjuvant and three neo-adjuvant chemotherapy. On average, women adhered to > 80% of their intervention sessions and complied with 76% of their walking targets, with the majority walking four days a week at moderate intensity for 30 minutes per session. Meaningful improvements were found in physical functioning, physical symptoms, physical well-being and ovarian cancerspecific quality of life. Most women (76%) completed ≥85% of their planned chemotherapy dose. There were no withdrawals or serious adverse events and all women reported the program as being helpful. Conclusions: These positive preliminary results suggest that this walking intervention for women receiving chemotherapy for ovarian cancer is safe, feasible and acceptable and could be used in development of future work. Trial registration: ACTRN12609000252213

Information interventions for orienting patients and their carers to cancer care facilities

Background: Cancer patients experience distress and anxiety related to their diagnosis, treatment and the unfamiliar cancer centre. Strategies with the aim of orienting patients to a cancer care facility may improve patient outcomes. Although meeting patients' information needs at different stages is important, there is little agreement about the type of information and the timing for information to be given. Orientation interventions aim to address information needs at the start of a person's experience with a cancer care facility. The extent of any benefit of these interventions is unknown. Objectives: To assess the effects of information interventions which orient patients and their carers/family to a cancer care facility, and to the services available in the facility. Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 2); MEDLINE (OvidSP) (1966 to Jun 2011), EMBASE (Ovid SP) (1966 to Jun 2011), CINAHL (EBSCO) (1982 to Jun 2011), PsycINFO (OvidSP) (1966 to Jun 2011), review articles and reference lists of relevant articles. We contacted principal investigators and experts in the field. Selection Criteria: Randomised controlled trials (RCTs), cluster RCTs and quasi-RCTs evaluating the effects of information interventions that orient patients and their carers/family to a cancer care facility. Data collection and analysis: Results of searches were reviewed against the pre-determined criteria for inclusion by two review authors. The primary outcomes were knowledge and understanding; health status and wellbeing, evaluation of care, and harms. Secondary outcomes were communication, skills acquisition, behavioural outcomes, service delivery, and health professional outcomes. We pooled results of RCTs using mean differences (MD) and 95% confidence intervals (CI). Main results: We included four RCTs involving 610 participants. All four trials aimed to investigate the effects of orientation programs for cancer patients to a cancer facility. There was high risk of bias across studies. Findings from two of the RCTs demonstrated significant benefits of the orientation intervention in relation to levels of distress (mean difference (MD) -8.96 (95% confidence interval (CI) -11.79 to -6.13), but non-significant benefits in relation to state anxiety levels (MD -9.77 (95% CI -24.96 to 5.41). Other outcomes for participants were generally positive (e.g. more knowledgeable about the cancer centre and cancer therapy, better coping abilities). No harms or adverse effects were measured or reported by any of the included studies. There were insufficient data on the other outcomes of interest. Authors conclusion: This review has demonstrated the feasibility and some potential benefits of orientation interventions. There was a low level of evidence suggesting that orientation interventions can reduce distress in patients. However, most of the other outcomes remain inconclusive (patient knowledge recall/ satisfaction). The majority of studies were subject to high risk of bias, and were likely to be insufficiently powered. Further well conducted and powered RCTs are required to provide evidence for determining the most appropriate intensity, nature, mode and resources for such interventions. Patient and carer-focused outcomes should be included.