Therapeutic misunderstandings in modern research.

Clinical trials play a crucial role in generating evidence about healthcare interventions and improving outcomes for current and future patients. For individual trial participants, however, there are inevitably trade-offs involved in clinical trial participation, given that trials have traditionally been designed to benefit future patient populations rather than to offer personalised care. Failure to understand the distinction between research and clinical care and the likelihood of benefit from participation in clinical trials has been termed the 'therapeutic misconception'. The evolution of the clinical trials landscape, including greater integration of clinical trials into healthcare and development of novel trial methodologies, may reinforce the significance of the therapeutic misconception and other forms of misunderstanding while at the same time (paradoxically) challenging its salience. Using cancer clinical trials as an exemplar, we describe how methodological changes in early- and late-phase clinical trial designs, as well as changes in the design and delivery of healthcare, impact upon the therapeutic misconception. We suggest that this provides an impetus to re-examine the ethics of clinical research, particularly in relation to trial access, participant selection, communication and consent, and role delineation.

Evaluation of Managing Cancer and Living Meaningfully (CALM) in people with advanced non-small cell lung cancer treated with immunotherapies or targeted therapies: protocol for a single-arm, mixed-methods pilot study.

INTRODUCTION: People with advanced non-small cell lung cancer (NSCLC) treated with immunotherapies (IT) or targeted therapies (TT) may have improved outcomes in a subset of people who respond, raising unique psychological concerns requiring specific attention. These include the need for people with prolonged survival to reframe their life plans and tolerate uncertainty related to treatment duration and prognosis. A brief intervention for people with advanced cancer, Managing Cancer and Living Meaningfully (CALM), could help people treated with IT or TT address these concerns. However, CALM has not been specifically evaluated in this population. This study aims to evaluate the acceptability and feasibility of CALM in people with advanced NSCLC treated with IT or TT and obtain preliminary evidence regarding its effectiveness in this population. METHODS AND ANALYSIS: Twenty people with advanced NSCLC treated with IT or TT will be recruited from Peter MacCallum Cancer Centre, Melbourne, Australia. Participants will complete three to six sessions of CALM delivered over 3-6 months. A prospective, single-arm, mixed-methods pilot study will be conducted. Participants will complete outcome measures at baseline, post-intervention, 3 months and 6 months, including Patient Health Questionnaire, Death and Dying Distress Scale, Functional Assessment of Cancer Therapy General and Clinician Evaluation Questionnaire. The acceptability of CALM will be assessed using patient experiences surveys and qualitative interviews. Feasibility will be assessed by analysis of recruitment rates, treatment adherence and intervention delivery time. ETHICS AND DISSEMINATION: Ethics approval has been granted by the Peter MacCallum Cancer Centre Human Research Ethics Committee (HREC/82047/PMCC). Participants with cancer will complete a signed consent form prior to participation, and carers and therapists will complete verbal consent. Results will be made available to funders, broader clinicians and researchers through conference presentations and publications. If CALM is found to be acceptable in this cohort, this will inform a potential phase 3 trial.

When research becomes practice: the concept of the therapeutic misconception and challenges to consent in clinical trials.

Many factors influence patients' decisions to participate in clinical trials. For many, the primary motivation is the possibility that they might derive some benefit from participation. This is particularly true for patients with limited treatment options, such as patients with advanced cancer. While this is not surprising, it is potentially problematic if patients fail to recognise the distinction between research and clinical care (a phenomenon known as the 'therapeutic misconception'). This is becoming increasingly problematic as clinical trial designs become more complex, as clinical trials become more embedded in routine clinical care, and as trials are increasingly used by patients and clinicians to access new diagnostic platforms and therapies. We outline some of these recent trends, focusing on the cancer clinical trials landscape as this provides a good case study of the phenomenon. We conclude by making preliminary suggestions that changes to the consent process, perhaps using 'dynamic consent' platforms, might help to mitigate the therapeutic misconception and note the need for further research to guide strategies for improving communication and decision-making.

Entanglements and imagined futures: The subject(s) of precision in oncology.

Precision oncology holds an increasingly powerful social function. In the era of precision, how people encounter, live with, and experience cancer, how they imagine their lives, how they navigate treatment regimens, and experience side effects, have been radically transformed. Innovations in oncology - in this case precision-related - are always more-than-clinical; their circulation exceeds the laboratory and the hospital, but what this 'circulation of innovation' produces has been thus far opaque. To begin to comprehend what is emergent at the cancer-precision nexus in people's everyday lives, we draw on qualitative interviews with twenty people diagnosed with metastatic non-small cell lung cancer undergoing immunotherapy and/or targeted therapy and we discuss how precision inflects survivorship, entangles subjects in chronic living, and induces novel temporalities. Through such inflections of survivorship, precision innovation re-shapes expectations and possibilities, and sometimes enacts new, unexpected (or, for some, unwanted) futures. Such illness and survivorship narratives indicate the importance of orientating the social science scholarship toward considerations of temporality and entanglements for comprehending precision innovation in oncology. And in doing so, provide a nuanced account of how innovations unsettle and recast, rather than unravel, the normative scene of cancer.

Hemophagocytic lymphohistiocytosis (HLH) and cytokine release syndrome (CRS) in a patient with oncogene-addicted metastatic non-small cell lung cancer (NSCLC) following combination chemotherapy-immunotherapy.

Immune checkpoint inhibitors (ICIs) are utilized in a variety of clinical settings for the management of patients with metastatic non-small cell lung cancer (mNSCLC). While any organ may be subject to immune-related adverse events (irAEs) as a consequence of ICI therapy, hematological irAEs are uncommon. We describe a scenario involving a patient with oncogene-addicted mNSCLC who experienced the rare, life-threatening complication of hemophagocytic lymphohistiocytosis (HLH) and cytokine release syndrome following the receipt of the IMPower150 regimen (carboplatin/paclitaxel/atezolizumab/bevacizumab) after progression on initial tyrosine kinase inhibitor therapy. Malignancy-associated HLH, while previously described, is more typically associated with hematological rather than solid cancers and has only very recently been reported among patients receiving ICIs. While identification of hemophagocytosis on bone marrow examination is pathognomonic, this feature is not essential for confirming a diagnosis of HLH. Prompt recognition of suspicious laboratory and clinical features by medical oncologists and engagement with other relevant disciplines is hence critical to ensure optimal management of the condition.

Developments in systemic therapies for the management of lung cancer.

Lung cancer accounts for approximately 1 in 10 new cancer diagnoses annually and is responsible for the most cancer-associated deaths in Australia. Despite such figures, there is reason for optimism with many practice-changing developments to report for the management of patients with thoracic malignancies over the last few years. We outline such changes, including the emerging role of immunotherapy in the neoadjuvant and adjuvant setting for patients with localised non-small-cell lung cancer, as well as the established standard of consolidation immunotherapy following definitive chemoradiotherapy for those with locally advanced disease. In the metastatic setting, combination chemotherapy-immunotherapy approaches have become the new paradigm for most patients in the absence of a recognised driver mutation. A range of novel targeted therapies now exist and are Pharmaceutical Benefits Scheme (PBS)-subsidised for targets such as EGFR, ALK and ROS1, with many others, such as KRAS G12C, NTRK, MET, RET and HER2, also with therapies rapidly being developed. Even among patients with small-cell lung cancer, who account for the worst prognoses and until recently have received a chemotherapy regimen that has remained unchanged in over 20 years, there is a new standard-of-care in combination chemotherapy-immunotherapy. Furthermore, immunotherapy and potentially anti-vascular endothelial growth factor agents now also play a role in mesothelioma treatment. Last, given recent developments in immunotherapy, targeted therapy and combination approaches in the non-small-cell lung cancer space, there is an increasing recognition of the diversity of lived experience for such patients and need for survivorship programmes to acknowledge such nuances.

Risk factors associated with suicide in adolescents and young adults (AYA) with cancer.

BACKGROUND: Higher rates of death by suicide are recognized both in individuals of any age with cancer and, separately, among adolescents and young adults (AYA) without cancer. Given this intersection, identifying risk factors associated with suicidal risk among AYA with cancer is critical. OBJECTIVE: To identify characteristics associated with suicide among AYA with cancer. METHODS: A retrospective analysis of AYA (aged 15-39) during 1975-2016 from the Surveillance, Epidemiology, and End Results database was conducted. Clinical and demographic factors associated with death by suicide among the AYA cancer population were compared to (i) US population normative data (standardized mortality ratios [SMRs]) and (ii) other AYA individuals with cancer (odds ratios). RESULTS: In total, 922 suicides were found in 500,366 AYA with cancer (0.18%), observed for 3,198,261 person-years. The SMR for AYA with cancer was 34.1 (95% confidence interval [CI]: 31.4-36.9). Suicide risk was particularly high in females (SMR = 43.4, 95% CI: 37.2-50.4), unmarried persons (SMR = 50.6, 95% CI: 44.7-57.1), those with metastatic disease (SMR = 45.2, 95% CI: 33.1-60.3), or certain histological subtypes (leukemia, central nervous system, and soft tissue sarcoma). Risk generally reduced over time, however remained elevated ≥5 years following a cancer diagnosis (SMR > 5 years = 28.1, 95% CI: 25.4-31.0). When comparing those who died from suicide and those who did not, the following factors demonstrated significant associations: sex (males > females), race (White ethnicity > Black/other ethnicity), relationship status (never married > other), and disease stage (distant > localized). CONCLUSIONS: Death due to suicide/non-accidental injury is high compared to normative data, requiring increased awareness among health-care providers, suicide risk monitoring in AYA, and appropriately tailored psychosocial interventions.

Supporting cancer care clinicians to 'hold' their patients during and beyond the COVID-19 pandemic: a role for reflective ethics discussions.

The COVID-19 pandemic has placed an overwhelming burden on healthcare delivery globally. This paper examines how COVID-19 has affected cancer care clinicians' capacity to deliver cancer care in the Australian context. We use the lens of 'holding patients' (drawing from attachment theory, psychology and from Australian Indigenous knowledge) to conceptualise cancer clinicians' processes of care and therapeutic relationships with patients. These notions of 'holding' resonate with the deep responsibility cancer care clinicians feel towards their patients. They enrich ethical language beyond duties to benefit, avoid harm, respect patients' autonomy and provide just treatment. We consider the disruptive effects of COVID-19 on care delivery and on clinicians themselves. We then show how models of clinical ethics and other similar reflective discussion approaches are a relevant support mechanism to assist clinicians to process and make sense of COVID-19's disruptions to their professional ethical role of holding patients during and beyond the pandemic.

Living with and beyond metastatic non-small cell lung cancer: the survivorship experience for people treated with immunotherapy or targeted therapy.

PURPOSE: Immunotherapy (IT) and targeted therapy (TT) have improved survival for some patients with metastatic non-small cell lung cancer (NSCLC). Their lived experience is under-studied. We conducted a single centre, qualitative study to understand concerns and unmet needs amongst this novel survivor population. METHODS: Eligible participants had metastatic NSCLC, aged >18, English-speaking and >6 months post initiation of IT/TT without progressive disease. Semi-structured interviews focused on physical, psychological, social and functional impacts of diagnosis, therapy and prognosis. Interviews were recorded and transcribed. Data were analysed via qualitative thematic analysis. RESULTS: Between May and December 2019, 20 participants were interviewed: median age 62 (range 34-83), 13 (65%) female; median time since diagnosis of metastatic NSCLC 27 months (range 10-108). Twelve out of 20 (60%) participants had a targetable mutation (EGFR/ALK/BRAF); 6 were receiving IT, 11 TT, 2 IT + chemotherapy and 1 IT + TT. Four main themes were identified: living long-term on IT and TT (chronic toxicities), psychological concerns (living with uncertainty, fear of cancer progression, scan-related anxiety), support with practical issues (finances, employment amidst prognostic uncertainty, challenges with trial participation) and wanting information pertinent to NSCLC subtype. CONCLUSIONS: Longer-term survivors of metastatic NSCLC experience significant physical, psychological and functional concerns and unmet needs. Results will inform a broader cross-sectional survey and resources to address the needs of this growing survivor group. IMPLICATIONS FOR CANCER SURVIVORS: A 'one-size-fits-all' approach to NSCLC survivorship is no longer appropriate. Survivors of metastatic NSCLC treated with novel therapies may benefit from specific information regarding long-term toxicities and psychological supports.

Alectinib induces marked red cell spheroacanthocytosis in a near-ubiquitous fashion and is associated with reduced eosin-5-maleimide binding.

We reviewed haematological investigations for 43 patients treated at a single centre with alectinib, an inhibitor of anaplastic lymphoma kinase (ALK) which is considered standard first-line treatment for patients with ALK-rearranged advanced non-small cell lung cancer. Ninety-five percent of patients developed marked acanthocytosis, echinocytosis and/or spheroacanthocytosis, not observable with prior treatment with other ALK-inhibitors. Anaemia developed in 73% of patients (38% <100 g/L, 8% <80 g/L), though definite new haemolysis was present in only 11%. Eosin-5-maleimide binding was reduced in all assessed patients, and increased membrane cholesterol was identified in one patient assessed with lattice light sheet microscopy. We have identified a previously undescribed phenomenon whereby alectinib induces red cell membrane abnormalities in nearly all patients through an unclear, but likely ALK-independent, mechanism, resulting in mild anaemia without universal haemolysis.

An exploration of the perceptions, experience and practice of cancer clinicians in caring for patients with cancer who are also parents of dependent-age children.

BACKGROUND: Being a parent alongside a cancer diagnosis presents unique challenges. It is unclear to what degree parenting considerations feature in routine care and how doctors approach treatment decision discussions. OBJECTIVE: To explore doctor perspectives regarding patients with cancer who have dependent children. METHODOLOGY: Focus groups and interviews conducted to ascertain doctor views. Responses were audio-recorded, transcribed and thematically analysed. RESULTS: Twenty-eight doctors participated: medical oncology (7), haematology (10), palliative care (8), and psycho-oncology (3). Participants observed cancer impacted upon parenting across several domains: psycho-social, practical, and family implications. Having dependent children was perceived to influence the patient experience and decision-making by patients and clinicians. Participants identified this cohort as emotionally demanding to care for with a range of psychological effects identified for doctors, particularly in highly challenging circumstances (single-parent and non-English speaking families, scenarios involving communication difficulties). CONCLUSION: Participants recognised the presence of dependent children to profoundly influence the experience of being both a parent and a patient with cancer. Identifying patients with parental responsibilities was noted as relevant for management at diagnosis through to death. Greater understanding of doctors' experiences providing care for this cohort may inform the development of resources to assist doctors and their patients.