Living with Metastatic Cancer: A Roadmap for Future Research

Simple Summary Although people with metastatic cancer are living longer with their disease, they are faced with challenges that can interfere with their quality of life. These challenges include worsening disease, survival time, symptoms, distress, and financial problems. The aim of this review paper is to describe a framework to guide future efforts to address these challenges. The framework includes the risk factors (predisposing factors), triggers (precipitating factors), and responses (perpetuating factors) that contribute to the onset and maintenance of problems in living with metastatic cancer. We conclude by suggesting areas for future work to prevent problems, manage triggers, and reduce unhelpful responses. Abstract Living with metastatic cancer, or metavivorship, differs from cancer survivorship and has changed as novel treatments have increased survival time. The purpose of this narrative review is to describe factors that impact challenges in metavivorship within a conceptual framework to guide future research. This review focuses on the specific metavivorship outcomes of progressive disease, survival time, symptoms, distress, financial toxicity, and quality of life. We describe the predisposing, precipitating, and perpetuating (3P) model of metavivorship. Understanding the biological, psychological, and social 3P factors that contribute to the development and maintenance of challenges in metavivorship provides a roadmap for future research. Implications of this model include prevention by targeting predisposing factors, management of precipitating factors after onset of metastatic disease, and treatment of perpetuating factors to reduce symptoms and improve quality of life during the chronic phase of metavivorship. This can be accomplished through biopsychosocial screening efforts, monitoring of patient-reported outcomes, education and communication interventions, interdisciplinary symptom management, advance care planning, and behavioral interventions to cultivate psychological resilience.


Introduction
In 2006, the Institute of Medicine published a seminal report entitled "From Cancer Patient to Cancer Survivor: Lost in Transition" that described the challenges of transitioning from active cancer treatment to post-treatment survivorship [1]. Its emphasis on high quality survivorship care is as relevant today as it was when the report was published. However, a new group of people with cancer has since emerged: those living long-term with metastatic disease. Advances in immunotherapy and In the premorbid phase prior to diagnosis of metastatic or recurrent disease, predisposing factors are the sole contributor to risk for developing distressing symptoms. Precipitating factors begin in the acute phase, begin to decline in the early phase, but may vary throughout the chronic phase due to various treatments and disease monitoring. Perpetuating factors begin in the early phase and can sustain symptoms and affect quality of life throughout the chronic phase.
The 3P Model suggests that interventions can be implemented at each phase of illness. Targeting individuals at risk due to predisposing factors may prevent onset of metastatic disease or side effects of treatment. Following a diagnosis of metastatic disease and initiation of precipitating factors, effective management of precipitating factors may prevent the development of perpetuating factors. Finally, perpetuating factors may be addressed in the chronic phase with appropriate intervention. Identifying the predisposing, precipitating, and perpetuating factors that contribute to outcomes can inform treatment planning and decision making at each stage of metavivorship. but quality of life tends to be similar or better in those treated with anti-PD-1 compared to controls. We are not aware of published subgroup analyses in ICI trials to identify patients at risk for worse quality of life and patient-reported toxicities [39][40][41]. However, immune-related adverse events (irAEs) of ICIs are well-described, and subgroup analyses point to predisposing factors such as age, menopausal status, and pre-existing conditions. Any grade irAEs occur in about 72% of patients treated with single-agent ipilimumab, with 24% experiencing grade 3 or above [42]. Across ICIs, common irAEs include rash, pruritis, fatigue, nausea, and diarrhea. Additional irAEs include colitis, endocrinopathies, hepatitis, hypophysitis, pneumonitis, and thyroiditis [43,44]. Subgroup analyses indicate that older age was not associated with overall rate of (irAEs), but older patients were less likely to develop severe toxicities and less likely to need hospitalization, controlling for gender, performance status, season, and combination immunotherapy [45]. Sex was not associated with the rate of development of any irAEs, severe irAEs, or hospitalization in univariate or multivariate analyses [45]. Other studies have shown that menopausal status may moderate sex differences in irAEs, with premenopausal women more likely to experience toxicities [46]. Clinical predisposing factors for more severe ICI toxicity include sarcopenia, autoimmune disease, and poor kidney function [47][48][49][50], although data are mixed [45]. Because analyses have been conducted in clinical trials, data are largely lacking regarding comorbidities, autoimmune disease, and social determinants of health (e.g., insurance status). Although effectiveness and tolerability of ICIs are encouraging, there remains a need to understand how these outcomes translate to the experiences of those living with metastatic cancer.
Psychological predisposing factors also have a role in metavivorship. Depression may be a risk factor for cancer, especially lung and breast cancers [51][52][53][54][55]. Biobehavioral mechanisms for the link between depression and cancer risk have been hypothesized, including health behaviors such as tobacco use and exercise, and the impact of chronic stress on cortisol, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, inflammation, and the gut microbiome [53][54][55][56]. Similar mechanisms may be involved with depression, stress, and cancer progression [57]. Depression may also impact survival. Metavivors with decreased depression during a supportive-expressive therapy intervention had a median survival twice that of those who had increased depression (medial survival 53.6 months compared to 25.1 months) [58]. In addition to mood, personality appears to be an important predisposing factor in metavivorship. Higher conscientiousness and lower neuroticism are associated with better health behaviors of exercise and diet among cancer samples [59], and adherence to cancer screenings among people without cancer [60]. Lower neuroticism is also associated with lower depression at the time of diagnosis with non-metastatic cancer, and predictive of better quality of life and lower anxiety after 6 months [61]. In a sample that included metavivors, higher neuroticism and lower extraversion, agreeableness, and conscientiousness were associated with less exercise and higher comorbidities, depression, anxiety, and symptom-related distress [62]. Spirituality has also been linked to positive coping and better quality of life among people with cancer [63], and spirituality prior to a cancer diagnosis may impact psychological outcomes after diagnosis. Among women with non-metastatic breast cancer, lower spirituality prior to diagnosis may lead to spiritual struggle and difficulty with psychological adjustment in the year after diagnosis [64]. Mood, personality, and spirituality prior to a diagnosis of metastatic cancer may be important psychological predisposing factors, yet more research is needed to determine how these factors contribute to symptoms and quality of life throughout the phases of metavivorship.
Social predisposing factors in metavivorship include social well-being, stressful life events, and socioeconomic status. Social quality of life appears to have biological mechanisms as higher social well-being was related to less leukocyte proinflammatory and pro-metastatic gene expression among non-metastatic breast cancer patients after surgery [65]. In women with metastatic or recurrent cancer, those who had no trauma history had disease-free intervals twice as long as those with a history of traumatic life events (median of 62 months compared to 31 months) [66]. Traumatic and stressful life events also predispose metavivors to develop cancer-related distress and posttraumatic stress disorder (PTSD) or subclinical posttraumatic stress symptoms (PTSS) [67]. Further research is needed to determine the impact of prior trauma on cancer-related distress among metavivors treated with targeted and ICI therapies. In a survey of cancer patients receiving chemotherapy (68% with metastatic disease), stressful life events were associated with greater cancer-related distress along with additional risk factors such as low income, lower functional status, and greater comorbidity [68]. Financial toxicity, or the financial burden of cancer and treatment on patients and their family members, also has social predisposing factors. Identified risk factors in various cancer samples include younger age, female gender, racial and ethnic minority status, unemployment, absence of health insurance, and greater out of pocket health care costs [69][70][71][72][73]. Prevention efforts may target these social predisposing factors for disease progression, survival, distress, and financial quality of life.

Precipitating Factors
Precipitating factors are caused by disease and treatment. These may include inter-related biological, psychological, and behavioral factors. Notably, there is a large body of research in humans and animals indicating that biological changes due to cancer and its treatment (e.g., inflammation) can cause short-and long-term psychological and behavioral changes. Inflammation is a well-established driver of metastatic disease in breast cancer and melanoma [74]. For example, neutrophils produce a wide variety of proteins that stimulate tumorigenesis as well as tumor cell proliferation, migration, and invasion [75]. Among women with metastatic breast cancer, circulating tumor cells have been found to be associated with circulating C-reactive protein (CRP) and circulating interleukin-6 (IL-6), among other inflammatory markers [76]. Melanoma is characterized by high immunogenicity and chronic inflammation in the tumor microenvironment [77]. Higher circulating levels of CRP and IL-6 prior to treatment with ICIs appear to be poor prognostic indicators among patients with metastatic melanoma [74,78,79], although evidence is mixed [80]. These findings are consistent with a large body of research demonstrating high levels of inflammation and associated behavioral changes (e.g., depression, fatigue) prior to surgery and systemic therapy for a variety of cancer types [81]. Interestingly, chronic inflammation appears to cause fatigue at least in part due to reduced cellular energy availability [82,83]. Although inflammation is among the best-studied mechanisms of psychological and behavioral changes in cancer patients, a variety of other mechanisms are also relevant. Additional research across several tumor types in human and animal studies suggests that HPA axis dysregulation as well as metabolic competition between the tumor and the rest of the organism can cause depression and fatigue [84][85][86]. These relationships appear to occur at least partially independently of inflammation [82,85]. Regarding targeted therapy for metastatic breast cancer, limited data suggest that CDK4/6 inhibitors may cause upregulation of IL-6 and IL-8 by tumor cells [87,88], although increases in systemic inflammation have not been documented to our knowledge. While all-grade fatigue is among the most common symptomatic AEs of CDK4/6 inhibitors [89][90][91][92], the mechanisms are not clear. In contrast, there is a large body of evidence that PD-1 and CTLA-4 inhibitors cause systemic inflammation in metastatic melanoma [93], including higher circulating levels of IL-1ra, IL-6, and IL-17, which are associated with irAEs such as colitis and dermatitis [94][95][96][97][98]. Further research is needed to determine whether circulating inflammatory markers are also associated with behavioral changes, such as depression and fatigue, in patients treated with ICIs.
Precipitating factors may also include psychological reactions to diagnosis and treatment of metastatic cancer. Potentially distressing events include being informed of a terminal diagnosis, sudden physical changes due to treatment, and medical emergencies due to cancer or treatment toxicities [99]. For example, irAEs can be acute medical emergencies requiring hospitalization [100]. Additional potentially distressing events include waiting for results of disease monitoring imaging studies, receiving results indicating progressive disease, and symptom interference in daily life [101]. Uncertainty regarding prognosis is also relevant given the potential for exceptional response to targeted therapies and ICIs [102]. Qualitative findings indicate that women with metastatic breast cancer report substantial psychological distress due to uncertain prognosis and treatment trajectories, and functional difficulties in social roles and responsibilities [103]. In addition, a growing body of literature suggests that cancer-related experiences can be traumatic. In one study, 69% of metastatic lung cancer patients indicated that their diagnosis and cancer treatment qualified as traumatic stressors per Diagnostic and Statistical Manual of Mental Disorders-5th Edition (DSM-5) criteria. Moreover, those who reported traumatic cancer-related experiences also reported greater distress and worry about progression [104]. In a sample including 42% with metastatic disease, cancer-related traumatic stress symptoms were associated with worse sleep disturbance and pain [105]. These findings suggest that precipitating psychological reactions to potentially traumatic cancer-related events may contribute to PROs such as psychological distress and sleep disturbance. The impact of cancer-related events and emotional responses on PROs for metavivors should be examined in future research.
Social and environmental precipitating factors may vary in their impact throughout the early and chronic phases and include changes to social roles and functioning due to cancer and treatment, such as changes to work responsibilities or employment. One study of women with metastatic breast cancer found that 45% stopped working due to illness, and 58% reported a change in employment [106]; however, data were collected between 2006 and 2008, and rapidly changing treatment paradigms may have a different impact on employment now. Another study found that 87% of metavivors across diagnoses stopped working within 6 months of diagnosis [107]. Changes to employment can lead to financial burden and inadequate health insurance coverage, which can increase distress, reduce appropriate healthcare utilization, and negatively impact symptoms and quality of life [108]. Further research is needed to determine the impact of targeted therapies and ICIs on employment and subsequent financial quality of life among metavivors. Metavivors can also experience changes to engagement with important social activities, and changes in the amount of support provided by others. Disrupted social and recreational activities are associated with greater depressive symptoms among breast cancer metavivors [109]. Support provided by friends, family, and others may initially increase in the acute and early phases of metavivorship, but then decline over time [3,110]. Social support either with practical needs or emotional support is important for symptom management, and low social support is even associated with mortality [111][112][113].

Perpetuating Factors
Perpetuating factors are longer-term biological, psychological, behavioral, and social changes due to precipitating factors that can sustain or exacerbate poor outcomes. Perpetuating factors can start as precipitating factors and become chronic, or they can emerge in response to precipitating factors. Biological perpetuating factors can result from disease or treatment. Tumor(s) may have an ongoing biological impact in metavivors with stable or progressive disease. Interestingly, however, chronic circulating markers of inflammation (i.e., IL-6, CXCL1) were observed in mouse models even after tumor resection, suggesting long-term changes due to the cancer or surgery even when the tumor is no longer present [114]. Moreover, tumor mass was associated with anxiety-like behavioral changes, even after resection [114]. These findings suggest that metavivors with complete response may have chronic biological and behavioral changes due to cancer. Regarding perpetuating biological factors due to treatment, we are unaware of any data regarding long-term or late effects of anti-CDK4/6 or anti-PI3K agents in metastatic breast cancer. Data on long-term and late effects of ICIs in melanoma patients are limited to a few case studies demonstrating new irAEs after completion or discontinuation of therapy [115][116][117]. In light of the well-known inflammatory mechanisms of irAEs during ICIs [98], chronic inflammation following treatment is a plausible pathway. Notably, the accumulation of multiple or chronic low-grade toxicities can have a greater impact than time-limited, severe adverse events [118]. As the number of metavivors increases, long-term and late effects are an important area of study.
Psychological perpetuating factors are cognitive and behavioral changes made in response to precipitating factors. While these changes may help manage symptoms in the short-term, some can contribute to sustained symptoms and negatively impact quality of life in the acute and chronic phases of metavivorship. For example, increased attention to unusual physical sensations may be an impetus for seeking medical care and play an important role in an initial cancer diagnosis and monitoring during active treatment; however, continued hypervigilance can lead to chronic anxiety and panic [119]. The prevalence of panic attacks in metavivors is unknown. However, people with cancer are twice as likely to experience panic attacks as those in the general population [120]. PTSS such as intrusive thoughts about aversive cancer-related events, avoiding reminders of cancer, negative cognitive appraisals (e.g., fatalistic or hopeless beliefs), and hyperarousal (i.e., heightened psychophysiological reactivity) are experienced to some extent by most people who have had cancer [121], although the prevalence of cancer-related PTSD generally falls around 10% [67,101]. In metavivors, cancer-related PTSD may be more common, with small sample sizes of metastatic breast cancer and melanoma showing prevalence rates between 35 and 52% [122][123][124]. In general, cancer-related distress appears to peak at diagnosis and during active treatment, and decline over time. However, more severe distress predicts continued high symptom burden and later diagnosis of cancer-related PTSD, indicating that for some patients, symptoms do not subside [125,126]. Cognitive predictors of cancer-related distress include illness perceptions and coping. For example, among lung cancer metavivors [127] and newly diagnosed early stage breast cancer patients [128], depression and anxiety are associated with fatalistic beliefs about the controllability of cancer, beliefs that emotions contribute to the development of cancer, and anxious preoccupation (i.e., worrying). There is a growing body of evidence that these cognitive and behavioral responses are amenable to change after intervention, with subsequent improvement in PROs (e.g., distress, fatigue, sleep disturbance, cognitive impairment) [129][130][131].
There are several social and environmental factors that can perpetuate metavivors' PROs. Social support across all stages of metavivorship has important benefits for metavivors, including increased hope and lowered depressive symptoms [132]. However, several social challenges may develop, including social constraint from loved ones who find it too painful to discuss a range of important topics from the cancer itself to death and dying [103]. Metavivors may also choose to join metavivor-focused support groups. Although many metavivors seek support groups to gain comfort and companionship, they may also hear about traumatic medical events and grieve the deaths of fellow group members [133]. Metavivors also experience changes to their socioeconomic environment, including financial toxicity. Metavivors are particularly vulnerable to financial toxicity because targeted and ICI treatments are among the most expensive cancer therapies available [134,135]. Financial toxicity, in turn, places metavivors at greater risk for psychological distress compared to those with early stage disease [136]. Moreover, financial toxicity can lead to medication non-adherence and underutilization of health care services [136], which can exacerbate symptoms, morbidity, and mortality.

Implications
Clinical identification of predisposing, precipitating, and perpetuating factors affecting metavivors' PROs may lead to more effective prevention, management, and treatment. Comprehensive biopsychosocial screenings are a key tool for this purpose [137]. Biopsychosocial screenings can take the form of self-report questionnaires, medical tests and labs, data from wearables (e.g., fitness trackers), and/or an integration of data from multiple sources. Clinicians can use biopsychosocial screenings to identify metavivors' predisposing factors at the point of diagnosis or earlier (e.g., during cancer screenings, during prior treatments for non-metastatic disease), as well as to identify precipitating and perpetuating factors as they change throughout metavivorship. Thus, routine biopsychosocial screenings can identify ongoing and shifting opportunities for intervention. As a stark example, a study of more than 734,000 patients diagnosed with various cancers found that being married was more strongly associated with longer survival than chemotherapy after accounting for disease and treatment characteristics, and unmarried individuals were more likely to have metastatic disease [138]. Knowing this, marital status is one predisposing social factor that can be used to identify metavivors who could benefit from early referrals to services designed to enhance social support in an effort to mitigate these effects. This is true of other known predisposing factors as well (e.g., age, socioeconomic status, history of psychopathology). Notably, existing systems are already primed to incorporate biopsychosocial screening into metavivors' care. This is due in part to a major shift in patient-centered cancer care that occurred in 2015 with implementation of the American College of Surgeons Commission on Cancer's standard requiring routine distress screening in all cancer programs. As a result, cancer programs across the US were required to determine when, how, and how often to solicit PRO data related to distress from individuals receiving cancer care [139]. Implementation of this standard looks different across programs depending on a host of factors including treatment setting, types of cancers treated, institutional resources, and clinic workflows. Yet as a result, cancer programs have laid the groundwork to incorporate additional measures and data sources into routine distress screening protocols to form more comprehensive biopsychosocial screenings.
To facilitate biopsychosocial screening protocols, cancer programs may consider leveraging the rapid technological advances of the past several decades, such as eHealth. eHealth is the use of information and communication technologies to facilitate care, and examples include online patient portals, telemedicine, and smartphone apps [140,141]. A recent trial underscores the potential benefits of using eHealth to routinely monitor patients' side effects during cancer treatments; Basch and colleagues [142] randomized over 700 patients with advanced cancer undergoing chemotherapy to report on treatment side effects either on a weekly basis using tablet computers or at intervals determined by their providers. Nurses were alerted to severe or worsening symptoms by email. Relative to usual care, routine eHealth PRO monitoring was associated with less decline in quality of life, fewer emergency room admissions, longer treatment with chemotherapy, and longer survival (median five months survival benefit for metavivors) [142,143]. The observed survival benefit was later replicated in advanced lung cancer [144]. The benefits of routine eHealth PRO monitoring are attributed in part to early detection of side effects during treatment. In some cases, this resulted in early detection and resolution of potentially dangerous complications, resulting in better tolerability of chemotherapy and, therefore, a higher dose of treatment. As applied to the 3P Model, early detection of precipitating factors (i.e., side effects) using routine eHealth PRO monitoring led to early intervention, which may have buffered against the development of perpetuating factors and thus improved outcomes. Since this seminal study, multiple eHealth systems have been developed for monitoring PROs and other patient-generated data (e.g., from wearables) [140,141,145], and several cancer centers have integrated routine eHealth PRO monitoring into patient portals and electronic medical records to promote patient-provider communication, shared-decision making, and patient-centered care [146][147][148]. Importantly, eHealth offers the flexibility to tailor biopsychosocial screenings to individual patient and treatment-related characteristics (e.g., predisposing factors, precipitating factors such as disease characteristics and known side effects of treatment regimens), further promoting patient-centered care [137].
Research to identify treatments for reducing precipitating and perpetuating factors among metavivors is relatively limited [149]. Existing studies have sought to improve patient education and communication with medical providers at the point of metastatic diagnosis and during treatment using decision aids [150][151][152][153][154][155][156][157], communication aids [153,154], question prompt lists [150][151][152], and educational videos and handouts [155,157]. Results are mostly positive, indicating the efficacy of these interventions for improving patient-centered outcomes such as communication. However, several studies were conducted prior to recent treatment advances and improvement of metavivors' clinical outcomes. Thus, more research is needed to determine how education and communication interventions may best support metavivors in the context of targeted and ICI treatments and long-term metavivorship. Medical interventions are used in supportive and palliative care to manage symptoms such as depression, anxiety, pain, and sleep disturbance. Integration of early palliative care with tumor-directed treatment has been encouraged for a person-centered approach [158]. Compared to palliative care consultations, systematic integration of palliative care in oncology has shown a greater impact on quality of life for advanced cancer patients [159]. Current evidence-based interdisciplinary treatments for palliative care of cancer-related symptoms are presented in clinical practice guidelines such as from the American Society of Clinical Oncology [160] and National Comprehensive Cancer Network [161]. Ongoing research efforts are also exploring new opportunities for medical management of cancer-related distress and symptom burden. For example, emerging evidence suggests that a single high dose of psilocybin may produce lasting improvement in depression and anxiety in patients with terminal cancer [162], and cannabinoids are under investigation to reduce overall symptom burden among patients with advanced cancer [163]. Other studies mostly grounded in cognitive-behavioral therapy have sought to directly improve PROs including distress [164][165][166][167][168][169], quality of life [170][171][172][173][174][175], and side effects of metastatic cancer and its treatments [176][177][178][179][180]. Results suggest that evidence-based interventions are efficacious for improving PROs among metavivors. However, as before, more work is needed to verify that interventions to directly improve metavivors' PROs are efficacious in the context of cutting-edge treatments and long-term metavivorship.
Although some metavivors are living longer with their disease, metastatic cancer remains a terminal diagnosis; thus, advance care planning (ACP) including clarifying treatment goals and formal advance directive documentation may be helpful for metavivors and their family caregivers. ACP remains underutilized along with supportive and palliative care services [181]. Providers may hesitate to initiate ACP discussions due to concern about causing distress; however, a large prospective study of patients with advanced cancer and family caregivers found that end-of-life discussions with medical providers were not associated with increased risk of depression or worry [182]. In fact, discussions between patients and providers regarding goals of care were associated with fewer hospital admissions and less aggressive treatment near end-of-life [183,184], which may improve quality of life and reduce financial toxicity [185]. Bereaved family members also have better psychological adjustment when patients undergo less aggressive treatments near end-of-life [182]. The majority of research on ACP involves hospitalized patients and those near end-of-life [183][184][185][186]; however, goals of care can be an ongoing and evolving discussion throughout metavivorship. Further research is needed to determine the optimal timing of ACP discussions for metavivors and their family caregivers. In addition, a systematic review found disparities in access to hospice care and inconsistencies between end-of-life care and patient preferences among Hispanic and African American patients with advanced cancer [187]. These findings highlight a need for future research to improve equity in ACP discussions and end-of-life care. Certain cultural or religious influences can also impact ACP discussions and must be considered to ensure a holistic approach to end-of-life care [188]. An extensive discussion of ACP perceptions, barriers, and best practices is available from the National Cancer Institute [189].
As a final note, it is important to recognize that that are several psychological and behavioral protective factors that can improve PROs in metavivorship. Despite the challenges of living with a terminal illness, metavivors demonstrate incredible resilience in the face of uncertainty about the future. Practicing mindfulness, living consistently with one's values, physical exercise, and a nutritious diet all show promise for improving PROs in cancer [190,191]. Metavivors may also cultivate meaning through their choice of attitude, connections with others and the world, participation in activities, and considerations of their legacy [192,193]. Metavivors may engage in positive reinterpretation such as seeing the "silver lining" of difficult situations, emphasizing things that are within their control, and expressing gratitude for the everyday [194]. Hope (i.e., the desire or expectation for a positive outcome or lack of a negative outcome) is another important positive psychological construct that may help to explain how individuals adapt in the context of terminal illness. Literature suggests that hope persists in metavivors regardless of proximity to death [195][196][197], and hope is dynamic such that people who report more hope are more likely to incorporate relevant contextual information into goal appraisal, adjust their goals or develop new attainable goals, and work toward these goals [198]. Positive reinterpretation and optimism do have limits, especially when employed to avoid aversive yet reality-based thoughts and emotions such as fear and grief. Mindfulness and self-compassion may attenuate the impact of negative events while validating emotional experiences [199][200][201][202]. Among patients with hematologic cancer recovering from hematopoietic stem cell transplantation (HSCT), mindfulness and acceptance of thoughts and emotions was positively associated with psychological outcomes following HSCT [203]. Among patients with advanced cancer, there is growing evidence for the efficacy of meaning-enhancing interventions (e.g., meaning-centered psychotherapy, supportive expressive therapy) for improving PROs such as spiritual well-being, sense of meaning, and quality of life [149,204,205]. Thus, interventions focused on cultivating these protective factors may be a critical complement to interventions designed to reduce precipitating and perpetuating factors in metavivorship care.

Conclusions
In conclusion, metavivorship presents several challenges that differ from patients and survivors with earlier stage disease. Metavivors treated with novel targeted and ICI therapies are living longer with their disease yet are faced with uncertainty in their prognosis and length of survival, acute and chronic symptoms, psychological distress, and financial toxicity. Clinical trials and retrospective medial record reviews provide information regarding clinician-rated adverse events. However, further research is needed regarding patient-reported outcomes and factors that impact important outcomes for metavivors. We provide a biopsychosocial conceptualization of predisposing, precipitating, and perpetuating factors for the challenges of metavivorship. Prevention efforts may target those with risk factors that predispose metavivors to develop progressive disease, reduced survival, symptoms, and financial toxicity. These outcomes may be mitigated by managing precipitating events such as immune-related adverse events, acute psychological distress, and social challenges. After prevention and management efforts, treatments can be implemented for perpetuating responses such as cumulative effects of treatment, changes to cognitive and behavioral patterns, and social constraints and financial burden. Specific recommendations for future research and clinical interventions include biopsychosocial screening, monitoring of patient-reported outcomes, education and communication interventions, interdisciplinary symptom management, advance care planning, and behavioral interventions to cultivate psychological resilience. Such efforts have the potential to have a high impact on quality of life for the growing population of metavivors.