Carriers of germline mutations in the TP53 gene, encoding the cell-cycle regulator and tumour suppressor p53, have a markedly increased risk of cancer-related morbidity and mortality during both ...childhood and adulthood, and thus require appropriate and effective cancer risk management. However, the predisposition of such patients to multiorgan tumorigenesis presents a specific challenge for cancer risk management programmes. Herein, we review the clinical implications of germline mutations in TP53 and the evidence for cancer screening and prevention strategies in individuals carrying such mutations, as well as examining the potential psychosocial implications of lifelong management for a ubiquitous cancer risk. In addition, we propose an evidence-based framework for the clinical management of TP53 mutation carriers and provide a platform for addressing the management of other cancer predisposition syndromes that can affect multiple organs.
Combination chemotherapy can cause greater tumour cell kill if the drug dose is not compromised, while sequential single agent chemotherapy may allow for greater dose intensity and treatment time, ...potentially meaning greater benefit from each single agent. In addition, sequentially using single agents might cause less toxicity and impairment of quality of life, but it is not known whether this might compromise survival time.
To assess the effect of combination chemotherapy compared to the same drugs given sequentially in women with metastatic breast cancer.
We searched the Cochrane Breast Cancer Group Specialised Register, using the search terms "advanced breast cancer" and "chemotherapy", MEDLINE and EMBASE on 31 October 2013. The World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov were also searched (22 March 2012).
Randomised controlled trials of combination chemotherapy compared to the same drugs used sequentially in women with metastatic breast cancer in the first-, second- or third-line setting.
Two authors independently extracted data from published trials. Hazard ratios (HR) were derived from time-to-event outcomes where possible, and a fixed-effect model was used for meta-analysis. Response rates were analysed as dichotomous variables (risk ratios (RR)), and toxicity and quality of life data were extracted where available.
Twelve trials reporting on nine treatment comparisons (2317 patients randomised) were identified. The majority of trials (10 trials) had an unclear or high risk of bias. Time-to-event data were collected for nine trials for overall survival and eight trials for progression-free survival. All 12 trials reported results for tumour response. In the 12 trials there were 1023 deaths in 2317 women randomised. There was no difference in overall survival, with an overall HR of 1.04 (95% confidence interval (CI) 0.93 to 1.16; P = 0.45), and no significant heterogeneity. This result was consistent in the four subgroups analysed (risk of bias, line of chemotherapy, type of schema of chemotherapy, and relative dose intensity). In particular, there was no difference in survival according to the type of schema of chemotherapy, that is whether chemotherapy was given on disease progression or after a set number of cycles. In the eight trials that reported progression-free survival, 678 women progressed out of the 886 women randomised. The combination arm had a higher risk of progression than the sequential arm (HR 1.16; 95% CI 1.03 to 1.31; P = 0.01) with no significant heterogeneity. This result was consistent in all subgroups. Overall tumour response rates were higher in the combination arm (RR 1.13; 95% CI 1.03 to 1.24; P = 0.008) but there was significant heterogeneity for this outcome across the trials. In the seven trials that reported treatment-related deaths, there was no significant difference between the two arms, although the CIs were very wide due to the small number of events (RR 1.53; 95% CI 0.71 to 3.29; P = 0.28). The risk of febrile neutropenia was higher in the combination arm (RR 1.32; 95% CI 1.06 to 1.65; P = 0.01). There was no statistically significant difference in the risk of neutropenia, nausea and vomiting, or treatment-related deaths. Overall quality of life showed no difference between the two groups, but only three trials reported this outcome.
Sequential single agent chemotherapy has a positive effect on progression-free survival, whereas combination chemotherapy has a higher response rate and a higher risk of febrile neutropenia in metastatic breast cancer. There is no difference in overall survival time between these treatment strategies, both overall and in the subgroups analysed. In particular, there was no difference in survival according to the schema of chemotherapy (giving chemotherapy on disease progression or after a set number of cycles) or according to the line of chemotherapy (first-line versus second- or third-line). Generally this review supports the recommendations by international guidelines to use sequential monotherapy unless there is rapid disease progression.
Purpose
To explore in a sample of adult cancer patients: (1) the relative influence of initiation source, information format and consultation format on preferred approach to life expectancy ...disclosure using a discrete choice experiment (DCE); and (2) whether patient age, cancer type and perceived prognosis were associated with preferences within the three attributes.
Methods
A DCE survey of adult solid tumour and haematological cancer patients. Participants chose between three hypothetical scenarios about life expectancy disclosure consisting of three attributes: initiation source (i.e. doctor versus patient-initiated discussion), information content (i.e. estimate presented as best-worst-typical length of life case scenario versus median survival time) and consultation format (i.e. two 20-min versus one 40-min consultation). Respondents selected their most preferred scenario within each question.
Results
Three hundred and two patients completed the DCE (78% consent rate). Initiation source was the most influential predictor of patient choice. More preferred a doctor deliver life expectancy information as soon as it is available rather than waiting for the patient to ask (59% vs 41% z = − 7.396,
p
< 0.01). More patients preferred the two 20-min rather than the one 40-min consultation format (55% vs 45%,
z
= 4.284,
p
< 0.01). Information content did not influence choice. Age, cancer type, and patient-perceived prognosis were not associated with preferences.
Conclusion
Healthcare professionals should assess cancer patients’ preferences for engaging in life expectancy discussions as soon as they have this information, and ensure patients have adequate time to consider the information they receive, seek additional information and involve others if they wish.
Abstract Objective To test the effect of three questions (what are my options? what are the benefits and harms? and how likely are these?), on information provided by physicians about treatment ...options. Methods We used a cross-over trial using two unannounced standardized patients (SPs) simulating a presentation of mild-moderate depression. One SP was assigned the intervention role (asking the questions), the other the control role. An intervention and control SP visited each physician, order allocated randomly. The study was conducted in family practices in Sydney, Australia, during 2008–09. Data were obtained from consultation audio-recordings. Information about treatment options and patient involvement were analyzed using the Assessing Communication about Evidence and Patient Preferences (ACEPP) tool and the OPTION tool. Results Thirty-six SP visits were completed (18 intervention, 18 control). Scores were higher in intervention consultations than controls: ACEPP scores 21.4 vs. 16.6, p < 0.001, difference 4.7 (95% CI 2.3–7.0) and OPTION scores 36 vs. 25, p = 0.001, difference 11.5 (95% CI 5.1–17.8), indicating greater information provision and behavior supporting patient involvement. Conclusion Asking these three questions improved information given by family physicians and increased physician facilitation of patient involvement. Practice implications . These questions can drive evidence-based practice, strengthen patient–physician communication, and improve safety and quality.
To estimate scenarios for survival for women with metastatic breast cancer (MBC) who are starting chemotherapy.
We sought randomized, first-line chemotherapy trials for MBC published from 1999 to ...2009. We recorded median progression-free survival (PFS) and median overall survival (OS) and extracted the following percentiles (represented scenario) from each OS curve: 90th (worst-case), 75th (lower-typical), 25th (upper-typical), and 10th (best-case). We also estimated these scenarios for each OS curve by multiplying its median by four simple multiples: 0.25 (worst-case), 0.5 (lower-typical), 2 (upper-typical), and 3 (best-case). Estimates were deemed accurate if they were within 0.75 to 1.33 times the actual value.
From 36 trials (13,083 women), the mean for median PFS was 7.6 months (interquartile range IQR, 6.0 to 9.0 months), the mean for median OS was 21.7 months (IQR,18.2 to 24.0 months), and the mean for the ratio of median OS to median PFS was 3.0 (IQR, 2.4 to 3.5). The mean for each OS scenario was worst-case, 6.3 months (IQR, 4.8 to 7.5 months); lower-typical, 11.9 months (IQR, 9.9 to 13.2 months); upper-typical, 36.2 months (IQR, 31.1 to 41.3 months); and best-case, 55.8 months (IQR, 47.5 to 60.2 months). Simple multiples of the median gave accurate estimates of the worst-case scenario in 73% of OS curves, lower-typical in 97%, upper-typical in 95%, and best-case in 96%. OS was longer in trials with higher proportions of estrogen receptor-positive tumors (P = .001) and in trials of trastuzumab-treated human epidermal growth factor receptor 2-positive tumors (P = .001).
Simple multiples of an OS curve's median can accurately estimate typical (half to double the median), best-case (triple the median), and worst-case (one quarter of the median) scenarios for survival.
Importance
Patients’ are encouraged to participate in advance care planning (ACP) in order to enhance their autonomy. However, controversy exists as to what it means to be autonomous and there is ...limited understanding of how social and structural factors may influence cancer patients’ ability to exercise their autonomy.
Objective
The objective of this study is to explore oncologists’ and palliative care physicians’ understanding of patient autonomy, how this influences reported enactment of decision-making at the end of life (EOL), and the role of ACP in EOL care.
Design and setting
Qualitative semi-structured interviews were conducted with consultant oncologists (
n
= 11) and palliative medicine doctors (
n
= 7) working in oncology centres and palliative care units across Australia.
Results
We found that doctors generally conceptualized autonomy in terms of freedom from interference but that there was a profound disconnect between this understanding of autonomy and clinical practice in EOL decision-making. The clinicians in our study privileged care, relationships and a ‘good death’ above patient autonomy, and in practice were reluctant to ‘abandon’ their patients to total non-interference in decision-making. Patient autonomy in healthcare is bounded, as while patients were generally encouraged to express their preferences for care, medical norms about the quality and ‘reasonableness’ of care, the availability of services and the patients’ family relationships act to enhance or limit patients’ capacity to realize their preferences. While for many, this disconnect between theory and practice did not diminish the rhetorical appeal of ACP; for others, this undermined the integrity of ACP, as well as its relevance to care. For some, ACP had little to do with patient autonomy and served numerous other ethical, practical and political functions.
Conclusion
The ethical assumptions regarding patient autonomy embedded in academic literature and policy documents relating to ACP are disconnected from the realities of clinical care. Medical norms and professional boundaries surrounding ‘good deaths’ have a greater influence on care than patient preference. ACP programs, therefore, may be rejected by healthcare professionals as irrelevant to care or may have the unintended consequence of limiting patient autonomy when used as a professional tool to encourage a ‘right’ way to die. A singular focus on bureaucratic ACP programs, which reduce patient autonomy to a ‘tick box’ exercise, may fail to enhance EOL care in any meaningful way.
Patients are often not given the information needed to understand their prognosis and make informed treatment choices, with many consequently experiencing less than optimal care and quality-of-life ...at end-of-life.
To evaluate the efficacy of a nurse-facilitated communication support program for patients with advanced, incurable cancer to assist them in discussing prognosis and end-of-life care.
A parallel-group randomised controlled trial design was used.
This trial was conducted at six cancer treatment centres affiliated with major hospitals in Sydney, Australia.
110 patients with advanced, incurable cancer participated.
The communication support program included guided exploration of a question prompt list, communication challenges, patient values and concerns and the value of discussing end-of-life care early, with oncologists cued to endorse question-asking and question prompt list use. Patients were randomised after baseline measure completion, a regular oncology consultation was audio-recorded and a follow-up questionnaire was completed one month later. Communication, health-related quality-of-life and satisfaction measures and a manualised consultation-coding scheme were used. Descriptive, Mixed Modelling and Generalised Linear Mixed Modelling analyses were conducted using SPSS version 22.
Communication support program recipients gave significantly more cues for discussion of prognosis, end-of-life care, future care options and general issues not targeted by the intervention during recorded consultations, but did not ask more questions about these issues or overall. Oncologists’ question prompt list and question asking endorsement was inconsistent. Communication support program recipients’ self-efficacy in knowing what questions to ask their doctor significantly improved at follow-up while control arm patients’ self-efficacy declined. The communication support program did not impact patients’ health-related quality-of-life or the likelihood that their health information or shared decision-making preferences would be met. Satisfaction with the communication support program was high.
Given the importance of clarifying prognostic expectations and end-of-life care wishes in the advanced cancer context, the communication support program appears to be an effective and well-received solution to encourage early information seeking related to these issues though, its long-term impact remains unclear. The manualised nature of the intervention, designed with existing clinical staff in mind, may make it suited for implementation in a clinical setting, though additional work is needed to identify why question asking was unaffected and establish its impact later in the illness trajectory.
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