Addressing unmet needs for people with cancer cachexia: recommendations from a multistakeholder workshop

Abstract

In October 2020, LUNGevity Foundation hosted 75 participants for a comprehensive Unmet Needs Workshop focused on addressing the needs of patients with cancer cachexia and their caregivers. A unique aspect of this workshop was that it centred on the patient perspective and yielded active involvement of patients, caregivers, patient advocates, clinicians, scientists, investigators, industry representatives, and regulators. Participants met virtually to discuss the state of the science, identify clinical and research gaps, and develop concrete action plans. Three needs emerged: (i) need to expand education about cancer cachexia among patients, caregivers, and clinicians; (ii) need to increase evidence, resources, and insurance coverage for medical nutritional and physical therapy for patients with cancer cachexia; and (iii) need to refine preclinical research, definition, diagnostic criteria, biomarkers, clinical trial inclusion criteria, and clinically meaningful endpoints to develop and implement effective therapies. This paper summarizes the diverse perspectives presented during the workshop, describes the key themes, and outlines recommendations made by this multistakeholder group to effectively meet the needs of people with cancer cachexia and their caregivers. Patients with cancer often experience progressive weight loss.1 Indeed, unintentional weight loss often precipitates the first visit and subsequent diagnosis of cancer. Such weight loss, or cachexia, is particularly common in patients with cancers of the head and neck, lung, and gastrointestinal tract and contributes greatly to cancer morbidity and mortality, more so among the elderly.2, 3 Cachexia reduces appetite, social–emotional interactions, functional capacity, and quality of life, and up to a third of cancer deaths have been attributed to cachexia.4-6 Despite its impact on cancer, there are no widely approved, effective therapies for cancer cachexia, and perhaps consequentially, there is typically minimal discussion of cachexia symptoms or interventions between patients and clinicians, including physicians, physician assistants, nurse practitioners, nurses, dieticians, and physical and behavioural therapists. Furthermore, available supportive care varies greatly by clinician, institution, and payer, leading to disparate outcomes for patients. Filling these gaps in cachexia care would reduce patient and caregiver distress and improve cancer outcomes. Diagnostic criteria for cachexia vary somewhat, but a widely accepted consensus defines cachexia as >5% unintentional weight loss over 6 months with muscle mass loss, with or without fat loss, that leads to progressive functional impairment.1 Staging of cachexia is intended to represent its severity, understand who might benefit from targeted interventions, and guide treatment decisions for those at the end of life. While there are various approaches to the classification of patients, often cachexia is classified into three stages: pre-cachexia (weight loss of <5% with anorexia and metabolic changes), cachexia [weight loss of >5% or body mass index (BMI) < 20 kg/m2 with 2% weight loss, or sarcopenia with >2% weight loss, including poor oral intake and is often associated with systematic inflammation], and refractory cachexia (low performance status and life expectancy of <3 months). The latter is characterized by end-stage cancer and poor performance status and is typically thought of as unresponsive to cachexia-directed treatment.1, 5, 7 Weight loss and reduction in BMI are associated with shorter median survival times in patients with cancer, which is further exaggerated with more severe weight loss and lower BMI.8 Patients with cancer and combined weight and muscle loss experience the poorest survival outcomes irrespective of BMI,9 in part due to the necessity of dose reductions and modifications. Conversely, weight stabilization has been tied to improved outcomes in several studies.10, 11 The pathophysiology of cancer cachexia, although not fully understood, is due to a variable combination of reduced food intake and altered metabolism (e.g. inflammation, decreased anabolism, and excess catabolism), arising from complex interactions among the tumour, host neuroendocrine and immune systems, and cancer treatments.1, 2, 12, 13 It is further characterized by dysregulation of host metabolic processes at the cellular and molecular level, including mitochondrial dysfunction, glucose dysmetabolism, and unbalanced lipolysis and proteolysis.14, 15 While it is unlikely that a single agent will treat all aspects of this syndrome, recent cachexia research has identified specific biological, endocrine, and immune mechanisms that precipitate loss of body weight, skeletal muscle, appetite, and physical function.16 For example, factors produced by the tumour and by the host, including inflammatory cytokines, exosomes, small molecules, and microRNAs, signal on distant tissues to suppress food intake and induce catabolism of fat and muscle. Furthermore, comorbidities including depression, anxiety, frailty, hypogonadism, uncontrolled pain, and altered gastrointestinal function may exacerbate the weight loss and functional decline seen in these patients. Such complex pathophysiology involving multiple organ systems and diverse mechanisms across tumour types leads to heterogeneity in clinical presentation, course, and outcomes from this condition. This heterogeneity also impedes diagnosis, staging, clinical management, and the development of new cancer cachexia therapeutic strategies.17 Although cachexia is not reversible through improving nutritional status alone, early nutrition intervention to counter anorexia may slow cancer cachexia. However, to date, shortcomings in nutrition research in this patient population have stymied development of standardized, effective nutritional interventions.18, 19 Because there are currently no widely approved, targeted drug treatments, multiple professional societies have issued guidelines for best supportive care for cancer cachexia. These vary considerably by geographical region and society discipline, reflecting the insufficient evidence for specific interventions, low research activity, and paucity of clinical trials devoted to cachexia versus cancer overall. Indeed, few investigational drugs have been evaluated in clinical trials and with limited success.20-22 However, a recent uptick in cachexia-specific research has begun to yield a better understanding of its underlying pathophysiology, and clinical trials of targeted therapies have begun to increase rapidly. As research and development efforts advance in this space, there is an opportunity for the multistakeholder community—scientists, investigators, clinicians, patients, caregivers, patient advocates, industry partners, and regulators—to work collaboratively in addressing cancer cachexia. Recognizing this opportunity, in October 2020, LUNGevity Foundation hosted a comprehensive workshop focused on addressing the unmet needs of patients and caregivers dealing with cancer cachexia (Unmet Needs Workshop) (Figure 1). Seventy-five participants met virtually over 2 days to discuss the state of the science, identify clinical and research gaps, and develop concrete action plans to meet critical areas of need in cancer cachexia. A unique aspect of this workshop was that it centred around the patient perspective and yielded active involvement of every stakeholder, ensuring input from all. Workshop participants drew a clear picture of unmet needs, including lack of awareness among patients, caregivers, and clinicians, limited treatment options, and limited availability of supportive care, leading to a significant negative impact of cachexia on patients and their families. Participants focused on recommendations for action in three key areas: (i) expanding educational resources and awareness about cancer cachexia among key stakeholders; (ii) enhancing supportive care services including nutritional and physical therapy interventions for patients with cancer; and (iii) developing the evidence for pivotal clinical trials to support the development of effective therapies, including alignment on endpoints that meet patients' needs (Figure 2). This paper focuses on the context and content of these recommendations informed by each group's perspectives. During the workshop, patients with cancer described being aware of their early symptoms, including loss of smell and taste, loss of appetite, nausea and food aversion, and the subsequent weight loss, weakness, and unwelcome and unpleasant changes to their body's appearance. Even those with medical training often did not realize that this cluster of symptoms had a ‘label’ or diagnosis independent of their specific cancer diagnosis and believed the symptoms were attributable to their anti-cancer treatment alone rather than their underlying cancer. Workshop participants spoke of having no information about how cachexia would affect their bodies, self-image, or ability to engage in daily activities. They reported receiving no specific information on cachexia, rarely hearing the word. Patient participants indicated that, ideally, patients would be taught to recognize and report cachexia early and view it as an integral part of their underlying cancer occurring concomitantly with cancer treatments. Patient awareness of what to expect from cachexia could help set expectations for potential outcomes and mitigate some negative impacts, even providing some emotional relief for people when they understand what is happening. Patients also expressed a strong desire to participate in anti-cachexia trials. Caregivers described being aware of their loved one's anorexia, reduced strength and mobility, and progressive weight loss, recognizing these as signs of cancer mortality. Without understanding that these symptoms are related to the tumour, they would urge their loved one to eat, often to the point of conflict. Once a source of joy and social comfort, shared meals became a source of stress, guilt, and anxiety instead. Surviving family members described dismay and anger upon learning that this syndrome has a name and well-characterized biology that was never explained during cancer care. They expressed concern that the oncologist was potentially avoiding the conversation due to lack of available interventions or a lack of knowledge. Workshop participants who have cared for cancer patients emphasized the need to enhance education for clinicians to help them prepare their patients and families for the onset and impact of cachexia and provide appropriate palliative care. Additionally, they stressed the impact that cachexia can have on caregivers regarding stress and emotional distress. The consensus was that providing proper knowledge and guidance to caregivers could reduce familial strife, facilitate acceptance, and enable partnering for best supportive care and participation in research and trials. Caregivers expressed willingness to facilitate or participate in anti-cachexia clinical trials with their loved one. The complexity of cancer cachexia, lack of diagnostic criteria, and paucity of evidence to inform clinical practice guidelines continue to impede consistent diagnosis and management even among the expert cancer cachexia community. Despite significant progress in developing the discipline of palliative care in recent years, these services are not readily available. Clinicians noted gaps in training about cachexia and its clinical management, leading many medical oncologists to miss the diagnosis, recognizing cachexia only when people have become profoundly emaciated and weak. Furthermore, with no validated cachexia screening tool readily available for clinicians in oncology care and a lack of consistent malnutrition screening, there are significant gaps in detection and management of the syndrome for many patients.16 Among the cachexia academic community, there is significant enthusiasm for expanding awareness about cancer cachexia. Extending knowledge to primary care, community oncologists, patients, caregivers, and advocates is key to supporting the development of novel therapies, integration of supportive care, and implementation of care pathways that can successfully address the aspects of cancer cachexia most meaningful to the patient experience. To detect nutritional disturbances at an early stage, clinicians should regularly evaluate nutritional intake, weight change, and BMI, beginning with a cancer diagnosis and repeated depending on the stability of the clinical situation. Experts summarized the outcomes of anti-cachexia trials to date and outlined challenges that have beset previous trials and those that hinder planned studies. These include a lack of biomarkers to prognosticate, diagnose, stage, and monitor cachexia, heterogeneity in patient selection, bias against anti-cachexia trials in favour of anti-tumour trials, lack of appropriate infrastructure, and absence of clarity regarding meaningful clinical endpoints from the regulatory agencies. The relatively low research activity in cachexia relative to cancer overall was also cited as a potential barrier to identifying novel targets for therapy.16 Recommendations emerging from this discussion included the refinement of diagnostic criteria, development of biomarkers, organization of a cachexia-specific clinical trials consortium, engagement of regulators to facilitate robust trial designs, and continued prioritization of cachexia research by funding agencies. Regulatory officials pointed to challenges in selecting appropriate clinical assessments and outcomes for clinical studies, also noting that there are currently no validated surrogate endpoints approved for use in cancer cachexia clinical trials, and that there remains a lack of alignment among patients, researchers, and clinicians on what endpoints would be most meaningful in this setting. The discussion identified a need to improve the mechanistic understanding of cachexia in different cancer types and the development of clear diagnostic criteria. It was suggested that drug effectiveness measures could target specific cancer types and cachexia phenotypes. Moreover, regulators stressed the importance of defining issues that matter most to patients and their caregivers, including what constitutes a meaningful clinical benefit. Understanding clinical benefits ultimately will guide clinical trial endpoint selection and the development of clinical outcomes assessments to advance clinical trials. As discussed above, cachexia can have profound negative impacts on a patients' autonomy, daily function, and quality of life.1 Cachexia is underdiagnosed in patients with advanced cancer due to inconsistent or ineffective screening practices,23 limiting opportunities for intervention. Despite the clear ties between cachexia, adverse outcomes, and mortality among patients with cancer, many patients, caregivers, and clinicians lack awareness about this debilitating syndrome. Patients may be overwhelmed at receiving information about cachexia at their initial oncology appointments. However, workshop participants agreed that cachexia-specific education throughout the cancer journey is important to help patients and caregivers understand their experience. This was thought particularly important for patients suffering cancers with high cachexia prevalence, including most advanced and metastatic diseases. Educational materials should define the condition, highlight the key signs and symptoms of cancer cachexia, including involuntary weight loss and changes in food intake, and urge patients to seek nutritional counselling and supportive care from reliable sources vetted by qualified and regulated practitioners. To create awareness, educational materials must include consistent messaging and be made widely available at cancer centres, cancer care websites, including advocacy groups, major medical reference repositories, and National Cancer Institute (NCI) information sites. The content of such materials should be developed in collaboration with patients and caregivers, should include culturally appropriate, in-depth, evidence-based recommendations, and should be communicated per health literacy standards.24 Such information would provide a measure of autonomy and purpose in addressing nutrition and exercise, and may help educate caregivers about cachexia, providing more realistic expectations for both patients and family members/carers. Though empowering patients is an attractive strategy to address cachexia, the onus should not fall on the patient and caregiver. 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Once become implementation research will be to the and impact of different guidelines and these therapies on clinical gaps in and clinical knowledge were discussed at the workshop, including around preclinical research, lack of consensus on the of cachexia, absence of validated biomarkers, of on appropriate criteria, and around clinically meaningful The was as the most significant in the of anti-cachexia therapies currently in addressing the were for developing effective in and research include developing and appropriate preclinical to provide evidence of potential to efforts are to of and of for these across in clinical research must be to enable pivotal clinical trials. validated cancer criteria are not and the of cachexia in in this While efforts are to this definition, its shortcomings create challenges for clinical trial and criteria in the may be to cachexia, identify patients at of cachexia, cachexia, and treatment These could include physical functional studies, or even measures For robust trials, cancer cachexia trial should for (e.g. tumour and factors (e.g. BMI, nutritional and of weight loss or functional and (e.g. of therapy and to to potential interventions, there must be some consensus regarding what potential clinical trial endpoints would be clinically multiple primary and endpoints are included in cachexia to the and of Such endpoints include muscle body strength or physical anorexia and quality of life, cancer treatment and To date, regulatory have indicated that measures of skeletal muscle mass are not as primary endpoints as they provide no of clinical benefit. function including have to clinical outcomes in this condition. to physical performance or have not been validated in this more clinical in patients with cancer cachexia to potential their minimal clinically important and inform clinical trial the patients' more work is to define what is meaningful to including to how an intervention might how they function, and Moreover, must not an on these patients and often therapies and should be limited to those for and effectiveness of the therapies. Cachexia remains a significant for many patients with cancer and their caregivers. The lack of awareness and understanding of cachexia among patients and their clinicians is an that can and should be with multistakeholder collaboration and Additionally, ensuring that all patients who need nutritional and support services them should be an the potential for benefit and low of The remains focused on the of developing novel for cachexia to improve clinically meaningful on the outcomes, the a clear to action for the community to advance progress in these to define and measure what most to patients with cachexia and their caregivers, from the patient and regulatory can improve the of people with cancer. 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