Cancer immunotherapy has revolutionised survival outcomes in patients to the extent that it is now recognised as one of the major modalities of cancer treatment. Technologies leading the charge are immune checkpoint inhibitory antibodies, chimeric antigen receptor T-cells and recombinant bi-specific T-cell engager molecules. It is thought that their workings depend on their effectiveness on specific immune recognition of cancer cells by cytotoxic T lymphocytes. For immune checkpoint inhibitory antibodies, anti-cancer activity results either from generation of new cytotoxic T lymphocytes specificities or re-invigoration of pre-existing intra-tumoral cytotoxic T lymphocytes. For chimeric antigen receptor T-cells and bi-specific T-cell engagers, genetic engineering re-directs anti-cancer activities of either exogenously delivered T cells or endogenous T cells, respectively. Even so, we must acknowledge the enormous complexity of human immunity and our relatively poor understanding of it. Although our current state of knowledge tells us that combination immunotherapies will be most effective, it does not inform us which combinations will optimise clinical benefit. Consequently, empirical clinical testing of cancer immunotherapies will likely continue in tandem with improved understanding of immunobiological mechanisms of action. Here, we aim to describe key principles of cancer immunotherapy and explain the rationale underlying current use of several different kinds of immune-active agents.
Two of the most common cancers, breast and bowel cancer, seem 'immune' to immune therapy but there are particular molecular subtypes of these cancers that are more responsive. Several types of cancer that occur rarely or uncommonly may also benefit from immune therapy. The rare cancers suffer from under-representation in phase 3 randomised controlled trials, as conducting such large scale studies in the setting of rare cancers is usually not feasible. This in turn affects regulatory approval and access to checkpoint inhibitors for these tumours. Nevertheless, reported activity of these drugs has led oncologists and patients to consider such therapy, particularly where no other active or effective therapy exists. This review article will review the evidence that supports immune therapy for such cancers.
The prognosis of patients with metastatic melanoma in Australia has changed dramatically since the introduction of immune checkpoint inhibitors. Ipilimumab, which targets cytotoxic T lymphocyte-associated protein 4 (CTLA-4) was the first agent introduced on the scene. Subsequently nivolumab and pembrolizumab which bind to the programmed death protein 1 (PD-1) have proven to be more effective and less toxic than ipilimumab and form the mainstay of treatment for patients with advanced melanoma. The combination of nivolumab or pembrolizumab with ipilimumab have resulted in improved response rates and survival outcomes with the cost of added immune mediated toxicities. Recently reported trials have shown benefit of adjuvant immunotherapy post resection of high-risk disease. This review will explore the pivotal clinical trial data that has led to regulatory approval for use of these immunotherapy agents in Australia and some of the clinical trial results currently reported for novel combination therapies.
Haematological malignancies are a heterogenous group of diseases mostly of immunological origin. Immunotherapies such as allogeneic stem cell transplantation and monoclonal antibodies have been an essential part of managing haematological malignancies for decades, though recent understanding of tumour and microenvironment biology has led to the development of highly effective targeted therapies. Inhibiting immune checkpoints such as programmed death-1 (PD-1) and its ligand (PD-L1) have yielded remarkable results in some highly refractory lymphoma subtypes such as relapsed classical Hodgkin Lymphoma. Autologous T-cells with chimeric antigen receptors (CARs) are highly effective in B-lineage acute lymphoblastic leukaemia (B-ALL) and appear promising in diffuse large B cell lymphoma (DLBCL) and myeloma. Bispecific antibodies such as blinatumomab are superior to salvage chemotherapy for relapsed/refractory B-ALL and have become standard of care. However, significant challenges remain in cost, deliverability and manufacture of some of these products. Certain haematological malignancies such as myelodysplastic syndrome and acute myeloid leukaemia remain poorly responsive to current immunotherapy, though new agents show promising pre-clinical data. Immunotherapy is a pillar of management for haematological malignancies and are likely curing a subset of patients previously considered incurable; the clinical challenge is determining how to employ these therapies for maximal benefit and minimal toxicity.
Lung cancer is the leading cause of cancer related mortality and the fifth most common malignancy in Australia. Most tumours are non-small cell histology, with small cell and making up a smaller fraction of newer diagnoses. Until recently, chemotherapy was the mainstay of treatment, with relatively modest benefits seen in progression free survival and overall survival. Immune checkpoint inhibitors including pembrolizumab, nivolumab and atezolizumab are monoclonal antibodies that inhibit the association of programmed death-1 (PD-1) and it's ligand, which is normally associated with malignancy-induced immunosuppression. There have been positive results in both the first and second line settings in metastatic NSCLC, changing the current treatment paradigm. PD-L1 testing remains a controversial predictive biomarker, used to stratify patients in several randomised phase 3 clinical trials. Current attention has shifted to combining different immune checkpoint inhibitors or in novel multi-modality combination with chemotherapy or radiotherapy. Immunotherapy has also entered into the management of stage 3 disease, and continues to be evaluated in the adjuvant and neoadjuvant settings. Toxicity remains favourable compared with conventional chemotherapy, although clinicians need to remain vigilant for rarer and severe immune related adverse events. It is an exciting time in thoracic oncology with improved and durable survival in this most lethal of malignancies.
Prostate, bladder, kidney, testis and penile cancers cause over 10% of all cancer deaths, and standard treatments are largely palliative in advanced or metastatic disease. Cancer immunotherapy has an established and rapidly expanding role in the management of genitourinary cancers, but the different cancers also give insights across the landscape of immunotherapy.Renal cancers can often have a well-established immune response, and can be poised for impressive responses to checkpoint immunotherapy. Combination immunotherapy will likely improve these 'fertile plains' further. The 'desert' of prostate cancer immunotherapy is currently hostile and unappealing, but vaccine strategies to increase immune recognition and novel checkpoint inhibitors are being explored to enrich this territory. Urothelial carcinoma is a veritable 'jungle' of therapeutic choices, where treatment individualisation and identification of new pathways to circumvent current pitfalls and improve outcomes. The largely unexplored zones of testicular germ cell and penile cancers suggest novel targets and complementary strategies to improve treatment.With several immunotherapies in routine clinical use for genitourinary cancer patients, immunotherapy has a solid footing, and many opportunities to explore new ideas and combinations to change the landscape of cancer immunotherapy and open new frontiers.
Immune checkpoint inhibitors are an integral part of cancer therapy following the demonstration of substantial responses across multiple tumour types. These agents induce T-cell activation against cancer cells that have achieved immune escape. Tipping the balance of immune homeostasis can however produce undesired autoimmunity, thus giving rise to a myriad of immune-related adverse events (irAEs) that can affect every organ. Although, mostly mild and manageable, potentially life threatening irAEs may occur and require prompt recognition and management.The incidence and severity of irAEs is likely to increase with combination immunotherapies. Clinical presentations of these irAEs are varied in onset, type and severity, often leading to delays in presentation, diagnosis and appropriate management. As immuno-oncology becomes integrated into the broader anti-cancer treatment paradigm, clinicians will be required to rapidly recognise and manage a wide range of irAEs. We provide a summary of the patterns of onset, key clinical, pathologic and radiologic features of irAEs and management guidelines. Successful management of irAEs requires education for the patient, their carers and other health personnel, good patient-physician communication and multidisciplinary input from the medical oncologist and other specialist.
Immunotherapeutic agents have shown impressive clinical efficacy in a broad range of tumour types, particularly in non-small cell lung cancer and melanoma. An effective predictive biomarker is needed to provide patients with the most effective available treatments, avoid unnecessary toxicity and improve cost effectiveness. While it has been an area of very active research in recent years, the ideal biomarker for predicting response to immune check point inhibitor therapy has not yet been universally agreed upon. Approaches to date have focussed on assessment of tumour related factors such as immunohistochemical expression of programmed death ligand-1 (PD-L1), mutational load and DNA mismatch repair gene or protein status. Alternatively, assessment of the immune microenvironment by techniques such as gene expression profiling or measurement of tumour infiltrating lymphocytes can also be informative. Identifying and validating effective biomarkers is particularly challenging for immunotherapy because the dynamic and multifactorial nature of the interaction between tumours and host immunity. In this review, we discuss the relative advantages and disadvantages of different biomarker approaches in the quest to identify a clinically effective predictive biomarker that can improve the overall utility for immune checkpoint inhibitors.
This review explores the evidence for a relationship between healthcare related financial concerns and advance care planning. Large-scale surveys of public opinion in the US have found that people perceive the financial domain to be an important aspect of quality of life and a major concern regarding end-of-life care, and qualitative research has found that financial worries have been found to be a distinct domain of patients' self-perceived burden on their family. Concerns about being a burden on others have some influence on treatment decisions and advance care planning. Healthcare related financial concerns have some basis in fact, as consumers' out-ofpocket costs continue to escalate in some countries. Further research is warranted about healthcare related financial concern and its impact on motivation for engaging in advance care planning, and the content of those plans. A conceptual model of the relationship is proposed to guide further research. This includes three sets of variables: person characteristics such as health literacy, marital/family status and health state; the trait or state of healthcare related financial concern; and behavioral outcomes such as advance care planning and treatment decisions.
The impact of a breast cancer diagnosis goes beyond the early diagnosis and treatment phases. While survival has improved significantly over the last decade, women report ongoing quality of life (survivorship) concerns as a result of their diagnosis and treatment. There are many models of supportive care available in Australia, including those provided by specialist breast care nurses, general practitioners, peer support groups and cancer support agencies and councils, and more recently those provided through virtual platforms. Most models of care in Australia recognise the need to provide supportive care throughout the treatment trajectory and beyond, yet there remains an inconsistent pattern in providing coordinated supportive care post completion of acute treatment. This review provides a brief synopsis of some of the models of supportive care available within and outside of Australia.
Inclusion of economic evaluations alongside cancer clinical trials necessitates the collection and analysis of resource utilisation and cost data alongside outcomes. The purpose of this paper is to describe and discuss the measurement of cost in clinical studies, particularly resource utilisation. Cost data collection can be conducted retrospectively through linkage of treatment data with claims data, such as Medicare, or by patient recall (questionnaires). Prospective approaches include the patient diary. Measures and data collection tools are usually modified by researchers to fit the purpose and target population of their specific study. There is strong agreement on the inclusion of direct medical and non-medical costs in economic evaluations. The balance of opinion is that inclusion of indirect costs is appropriate; but agreement on exactly 'which indirect costs' and in 'what context' differs. However, narrow study perspectives mean that inter-sectoral resources are often overlooked. In addition to the two cancerspecific instruments included in the Database of Instruments for Resource-Use Measurement, there are numerous resource utilisation measurement tools used in a broad range of clinical research with heterogeneous intervention characteristics and outcome measures. Despite this, very few studies report validated cost/resource use instruments. Further, many cost analyses ignore long-term care costs, nonmedical costs borne by patients and important costs incurred in other sectors, such as social services. There is no 'gold standard' for resource utilisation instruments and the agenda for future research is lengthy. For example, many issues such as recall length, accuracy in recall of medical terms and medicines, specificity versus comprehensiveness of the instrument and missing data, remain to be addressed. Innovation in mobile technology will likely revolutionise data collection and may overcome many of the existing barriers to robust measurement of resource utilisation for cancer clinical trials and improve societal decision making.
While financial toxicity due to the high costs of cancer treatment is increasingly recognised as a significant challenge for cancer patients and survivors, the impact of reduced work participation as a major driver of financial toxicity is only just coming to light. Unemployment and reduced employment after a cancer diagnosis is associated with reduced financial reserves, impaired quality of life, and possibly reduced survival. Loss of work after cancer disproportionally impacts on those already more vulnerable, such as low income employees and the very young, with impact persisting for some for many years. Research needs to focus on quantifying and predicting the impact of reduced work participation on quality and quantity of survival, and development of interventions to assist with meaningful work participation for cancer survivors.
Objective: To assess the feasibility of clinical application of recently produced Optimal Care Pathways and explore patterns of care for oncology patients receiving care based in the City of Greater Bendigo.Design, setting and participants: A retrospective audit of hospital administrative and medical records data undertaken at Peter MacCallum Cancer Centre (PeterMac) and Bendigo Health between January and June 2016. Eligible cases were PeterMac patients with a residential address in the City of Greater Bendigo and who received care based at the PeterMac Bendigo campus as a new patient between 01 January and 31 December 2015.Outcome measures: Congruence of routine care with timeframes for steps described in the Optimal Care Pathways for cancer patients commissioned by the Victorian Department or Health and Human Services.Results: Assessment of congruence of routine care to the Optimal Care Pathways was complicated by missing data. Where data were available, many pathways of care did not fit the Optimal Care Pathway process map template, due to screening-related or asymptomatic presentations or appropriate deviations in clinical management responsive to individual patient need.Conclusion: This study is the first to report feasibility of mapping routine care against the parameters recommended by the Optimal Care Pathways, and to provide guidance for the future assessment of usual care of cancer services to best practice guidelines.
In 2015, approximately 2.7 million Australians were unpaid caregivers, including partners, family members, friends and neighbours. However, the true population of Australian caregivers may be under-estimated due to lack of carer self-identification, and this may be even more so for Australians of culturally and linguistically diverse backgrounds and Aboriginal and Torres Strait Islanders. Increasing cancer incidence and survival has resulted in a corresponding increase in the demand for unpaid caregivers, prompting in-depth exploration of the economic, psychosocial and physical impact of caring. Caregivers' physical health is significantly impacted and is sometimes reported to be lower than the patients they care for, perhaps as a consequence of prioritising the patient's needs and health over their own. Caregivers are also at increased risk of poorer psychological outcomes than the general population, reporting high levels of depression and anxiety. The financial impact is significant, with informal caregiving representing 18-33% of the total financial cost of cancer. The burden of this financial responsibility can adversely impact caregivers' quality of life, limiting their capacity to fulfil other caregiving roles and also having a direct adverse impact on the patients' quality of life. This paper reviews the costs of caregiving, from a financial, physical and psychosocial perspective.
The Australian healthcare system aims to provide accessible healthcare to all citizens, and on a global scale it appears to achieve good health outcomes, with relative efficiency. However, the system is complex and despite various public funding programs, numerous out-of-pocket expenses to patients remain; in cancer patients these are estimated to be significant. The types of costs associated with healthcare are described here, as are the main public healthcare funding schemes in Australia. Decision-makers for these schemes do request information regarding patient costs in economic analyses, however the extent to which cost data are available is limited. Generally and primarily for the practical reasons-but sometimes with a philosophical consideration-only limited information on patient healthcare-related costs will have been considered before a funding recommendation is made. There is a concern that without increased consideration of patient costs, the existing network of public funding schemes in Australia may not adequately ensure the affordability of healthcare.
The escalating financial cost of cancer to patients and their families is emerging as a global phenomenon. Despite diversely funded healthcare systems internationally, cancer causes substantial financial burden to individuals in many different countries, including the USA, Canada and Ireland. Australia is no exception and the articles in this Forum explore the many facets of financial costs in this context.
The term 'financial toxicity' is broadly used to describe the distress or hardship arising from the financial burden of cancer treatment. In much the same way as physical side-effects of treatment like fatigue, nausea or blood toxicities, financial problems after cancer diagnosis are a major contributor to poorer quality of life, treatment non-adherence and delayed medical care. This article describes what financial toxicity is, how it is measured, how common it is and what the implications are for further research and clinical practice. A recent review shows a wide range of measures used to describe the financial burden of cancer. Using monetary measures, the magnitude of financial stress was between 28-48% in cancer populations. Possible solutions to reduce the family financial burden include mandating full disclosure of doctors' fees and charges related to treatment and strategies to empower patients to improve their treatment decision making. Furthermore, screening tools such as the COST-FACIT 11-item survey may assist health professionals to identify those patients at high risk of financial stress and refer them to support services. Minimising financial stress is important for patients and measuring financial toxicity helps to expose flaws in health systems and subsequently ensure that citizens receive quality cancer care.
More than 15,000 women are expected to be diagnosed with breast cancer in Australia in 2016. The shift towards delivering cancer care through ambulatory treatment centres means that partners, relatives, children, siblings and friends of women diagnosed with breast cancer are commonly required to provide much-needed care and support for these women post-treatment. The role of 'carer' can take many different forms and for some, it can be equivalent to a full-time job, with many carers reporting having more things to do than they can handle. Being a carer can be a positive experience, for example some husbands of breast cancer patients undergoing active treatment reported both interpersonal and intrapersonal benefits of caring, such as feeling closer to their partner and growing as a person. However, there is ample evidence that taking on the role of carer has significant impacts on carers' physical and mental health and many carers feel illprepared for that role, especially if the care requires them to address complex medical needs while also supporting their loved one with the psychological challenges experienced following a cancer diagnosis. The inter-relationship between patients' and carers' wellbeing is well-documented, with evidence suggesting that carers' physical and mental wellbeing may influence patient status. Hence, offering informal carers interventions that are structured, goal-oriented and time-limited is recommended to support them in their roles, and many argue that family carers should be considered a 'co-user', or 'co-client' of cancer services.
Chemotherapy-induced hair loss is a common and distressing side effect of some chemotherapy agents, and is ranked as one of the top three most distressing side effects by patients. Hair loss (alopecia) is more prominent on the scalp but affects the eyebrows, eyelashes, beard, axillary and pubic hair and typically begins within the first three weeks of starting chemotherapy. Patients report lower quality of life, high levels of distress, negative body image and feelings of loss of control associated with their alopecia. For most patients regrowth occurs after treatment completion but the colour and structure of hair can be altered, prolonging the negative impact on patient sense of wellbeing. The impact of chemotherapy-induced alopecia on patients is underestimated by many health professionals. Management is typically to camouflage the loss by wearing a wig, head scarf, or hat/turban. Scalp cooling with coolant based devices to reduce chemotherapy-induced alopecia has been available in Europe for more than a decade, but has only recently been introduced in Australia. Scalp cooling works by reducing local concentration of chemotherapy agents and decreasing metabolic uptake by hair follicle cells. Given the significance of hair loss to patients, further research to ameliorate this common side effect of chemotherapy treatment is urgently required.
