Lived experience of people with adrenocortical carcinoma and associated adrenal insufficiency

Abstract Introduction Adrenocortical carcinoma (ACC) is a rare cancer with an annual incidence of 0.7–2 cases per million population and 5‐year survival of 31.2%. Adrenal insufficiency (AI) is a common and life shortening complication of ACC, and little is understood about how it impacts on patients' experience. Objective To understand patients' lived experience of the condition, its treatment, care process, impact of AI on ACC wellbeing, self‐care needs and support. Methods Systematic review of MEDLINE, EMBASES, CINAHL, PsycINFO and Open Grey for studies published until February 2021. All research designs were included. The findings underwent a thematic analysis and narrative synthesis. Studies quality was assessed using mixed method assessment tools. Results A total of 2837 citations were identified; 15 titles with cohort, cross‐sectional, case series and case report study designs met the inclusion criteria involving 479 participants with adrenal insufficiency secondary to adrenocortical carcinoma (AI/ACC). Quantitative research identified impacts of disease and treatment on survivorship, the burden of living with AI/ACC, toxicity of therapies, supporting self‐care and AI management. These impact factors included adjuvant therapies involved and their toxicities, caregivers/family supports, healthcare and structure support in place, specialist skill and knowledge provided by healthcare professional on ACC management. No qualitative patient experiences evidence was identified. Conclusion ACC appears to have high impact on patients' wellbeing including the challenges with self‐care and managing AI. Evidence is needed to understand patient experience from a qualitative perspective.


| Background
Adrenocortical carcinoma (ACC) is a rare and usually aggressive cancer with poor outcomes for many patients. Its incidence worldwide is estimated to be around 0.7-2 cases per million per year in adult populations. 1,2 The median age at diagnosis is 56 years with women and white Caucasians being more frequently affected. 1,3 Patients with ACC often present with secretory tumours leading to Cushing's syndrome and/or androgen excess. 4,5 Survival depends on staging at presentation; overall median survival rate can be as low as 17 months. 1 The 5-year survival rate is 31.2%, and this has failed to improve from data collected between 1983-2009 1,2,6 despite advances in treatment.
Existing evidence indicates that people with adrenal disease have reduced quality of life irrespective of hypo, or hyperfunction. 7 People with ACC also have more unhealthy days, worse quality of life and mood scores, and higher odds of depressive symptoms compared to those with benign non-functioning tumours or benign hormonal disorders such as primary hyperaldosteronism, Cushing's syndrome, congenital adrenal hyperplasia and Addison's disease. 8 Clinical guidelines on the management of ACC acknowledged that there was a lack of evidence understanding the impact of ACC on an individual's life. 9 Surgical resection followed by adjuvant therapy with the adrenolytic agent mitotane has been the mainstay of treatment since the 1970s. 9,10 There is a role for chemotherapy and radiotherapy in addition. Patients with ACC treated with mitotane commonly develop toxicity, including adrenal insufficiency (AI) and individuals with preexisting cortisol excess may become glucocorticoid insufficient postoperatively. Several studies have found that 90/407 (22%) patients with ACC developed AI peri-or post-operatively following surgery and this incidence increased to 50% in the subgroup with cortisol secreting ACC. 10,11 Mitotane represent the first-line post-operative treatment with its adrenolytic properties. 12 Patients on long-term mitotane adjuvant therapy start to show biochemical evidence of AI within weeks to months into mitotane therapy. 13 Mitotane also induces the drug-metabolizing enzyme CYP3A4, increasing drug metabolism including that of glucocorticoids used to treat AI. 13 Several studies reported that higher replacement dose of glucocorticoid was required to treat AI related to ACC (AI/ACC) and to prevent adrenal crisis, compared with other causes of AI. [14][15][16] Whilst qualitative data on living with ACC is available, a scoping review revealed no qualitative patient experience evidence for living with AI related to ACC. 17 This systematic review aimed to understand patient lived experience and wellbeing in AI secondary to ACC using evidence from a variety of study designs and thereby extract evidence related to the impact and management of this condition on patient wellbeing to inform a holistic approach to person-centred care.

| Objectives
To systematically review the evidence to answer the following questions:  Table S1).

| Inclusion and exclusion criteria
Inclusion criteria were empirical studies of any design, published in English, involving patients of any age, including children, with AI/ ACC. Paediatric studies were included to understand the perspectives of carers/parents. Studies focused on patients with ACC management including lived experience and wellbeing outcomes were included where data on a subset of people with secondary AI were reported separately. Exclusion criteria were non-human studies.

| Screening
Identified citations were exported to Endnote. A total of 2827 citations were identified; 95 duplicates were removed; 2732 titles and abstracts were screened against eligibility criteria. No grey literature was identified for inclusion. 2642 titles were excluded at the title and abstract screen, 90 eligible full text papers were identified by investigator PY. 15 papers met the inclusion criteria (see PRISMA diagram Figure 1).

| Data extraction and synthesis
Results from the included papers were extracted to a table and include treatment regime, survivorship, side effects and toxicity experienced, patient reported outcomes, impact of clinical management and supports provided. Due to the heterogeneity of study designs, different population and assessment tools, meta-analysis was not possible and instead, narrative convergent synthesis was utilized to analyse the evidence. 18

| Study characteristics
The 15 studies included a total of 479 patients who had AI/ACC: 196 males and 283 females. The median age of the adult patients were 45 years with the youngest age 2 years and the oldest one age 79.6 years. 87% of the included patients were white Caucasian. 22 Studies were undertaken in Italy (n = 5), 13,24,25,30,31 France (n = 1), 28 Netherlands (n = 1), 23 Pan European Union involving Italy, France, Germany, and Netherlands (n = 1), 29 USA (n = 4), 21,22,26,27 Australia (n = 1), 16 Brazil (n = 1) 14 and Canada (n = 1). 15 The study designs consisted of nine cohort studies, 13,14,21,22,[24][25][26]28,29 four case reports, 15,16,30,31 one cross-sectional 23 and one case series. 27 All studies reported quantitative data published between 1994 and 2020. Cross-sectional or cohort studies had sample sizes ranging from 11-122, whereas case series had six patients and case reports had one to two patients ( Table 1, Table S3). Three studies recorded a frequency of surgeries, and out of 106 participants, 31 had two or more surgeries. 24,25,27 The multiple surgical experiences were illustrated in case studies. 15,16 In four studies that reported tumour metastasis, 73 out of 126 patients had more than one site. 21,24,25,27 Similar pattern was noted in nine studies that recorded tumour staging, 283 out of 297 patients had staging II or above. 13,14,22,24,[27][28][29][30][31] Table 2). 2 years was influenced by the consequences of coping with this condition. 16 Patients with ACC need to learn to cope with the disease and adhere to treatment progression while preparing for the possibility of facing palliative care. 14 Mitotane initiation to achieve therapeutic levels was challenging for some patients. It was reported that mitotane absorption was unpredictable. [14][15][16]31 One study was unable to find any significant correlation between the cumulative mitotane dose and the plasma mitotane level. 28 It took up to 15 months for some patients to achieve therapeutic mitotane levels, 18% patients discontinued mitotane treatment and 50% required transient discontinuation. 13,14,[22][23][24]28 The unpredicted side effects of mitotane coupled with its discontinuation created additional mental challenges of living with AI/ACC.

| Study themes
Carers of ACC patients were faced with extensive responsibilities such as providing personal care, medication adherence, symptoms management, understanding toxic drug side effects, learning to identify the need for glucocorticoid adjustment, knowing when to intervene to prevent adrenal crisis or administering hydrocortisone injections if adrenal crisis occurred. 14

| Toxicity of therapies
Patients who decided to undergo ACC treatments were faced with the symptoms of treatment toxicities which could have profound impact on their lives. [13][14][15][21][22][23][24][25][26][27][28][29] Those who endured chemotherapy for ACC were given a median of five to six cycles (range 1-16 cycles), respectively 24,26 with only 52.8% of the patients completing the treatment plan of six cycles. 24 Earlier findings reported that patient survival was influenced by achieving mitotane therapeutic levels (p = 0.01) and total resection at first surgery (p < .001). 23

| Supporting self-care
Self-care needs and deficits in patients living with AI/ACC was addressed in two of the case studies. 14,16 A patient was 'given education' on glucocorticoid replacement sick day rules following her first adrenal crisis. 16 The format and delivery of this education was unclear. Other case reports failed to describe if AI education to improve self-care was provided. 30,31 Complex self-care needs in relation to their oncological treatment and self-care activities were evidenced in five studies. 13,14,23,28,29 For example, mitotane was recommended to be taken orally with meals containing fat to improve absorption. 14 29 In one case study, initiation of mitotane therapy after ACC diagnosis was preceded by multidisciplinary and psychological support followed by palliative care. 15 These established pathways provided a structure allowing patients and their families to engage with their clinical care, while adopting a patient-centred approach.

| AI management
Patients started to develop AI within 3 months of taking mitotane 13 and in one study, all six patients became adrenal insufficient within 16 weeks. 27 The impact of AI could last several years after stopping mitotane. 31 Symptoms of adrenal crisis were experienced by 5/11 (45%) of patients who required prompt treatment with intravenous hydrocortisone and hydration. 14 Hydrocortisone omission during intercurrent illness resulted in 2/12 (16.7%) of patients' deaths from adrenal crisis. 14,16 Patient and families were unaware of the need to adjust glucocorticoid/steroid dosage required during illness. 14,16 This was highlighted by patients' experience where AI managements were complicated by the effects of mitotane and treatment modalities. 15,31 To reduce the risk of developing adrenal crisis, people with AI related to ACC need to be educated on the importance of glucocorticoid replacement. 13,15,16 Unfortunately, details of the education programs to address AI were absent among the reviewed studies. [13][14][15][16]28,30,31 Adding to this, many of the symptoms related to adrenal crisis resembled mitotane, chemotherapy or immunotherapy toxicities making patient AI focus approach most challenging. [13][14][15][16][21][22][23][24][25][26][27][28][29] 4 | DISCUSS ION

| Main findings
This systematic review demonstrates the limited evidence that underpins the effectiveness of support for self-care or management of survivorship in the light of excessive treatment burdens. The treatment, care process, quality of life, wellbeing, self-care needs and support did not provide rich narratives to reflect patients' overall experiences and wellbeing. This review identified the significant toxicity that people with AI/ACC endure, high healthcare burden and consequences related to AI/ACC followed by poor survival, self-care shortfall, impact on wellbeing and education needs. Treatment and care process were dominated by diagnosis and therapeutic efforts.
Fear and concerns with treatment and disease progression were not well addressed and consequently, give rise to research questions for the next empirical stage.

| Findings compared with wider evidence
A systematic review on quality of life of 323 patients with ACC concluded that they have worse quality of life scores compared with the general population. 36 Other studies found standard ACC treatments failed to improve the quality of life of patients, with 178/340 (52%) patients having ECOG scores from 1 to 4. 37,38 Patients with functional ACC were found to have other preoperative comorbidities such as diabetes, hypertension, congestive heart failure, obesity and coagulopathy, leading to post-operative complications, increased Charlson comorbidity index, tendency toward emergency operations and longer hospitalizations. 3 The impact of chronic comorbidities in ACC requires further investigations to understand the relevant contribution to overall morbidity among these coexisting conditions.

Recent qualitative interviews with 10 ACC patients identified
four domains related to their wellbeing. 17 They were physical complaints, mental consequences, social consequences and functional limitations. These concerns related to feeling insecure between radiological procedures, limitations with daily activities and mobility, experiences with healthcare system and professionals. AI data were not analysed separately from non-AI hence the study was not included in this systematic review. However, the study also found patient experiences and partner perspectives influences wellbeing.
The effect of a supportive partner was identified by another study which found marital status had positive association (p = .008) with ACC survival. 39 It has been suggested that this might be attributed by increased peer support for access to healthcare, treatment adherence and willingness to seek help. These findings align with the themes in our systematic review and reinforce the case for qualitative research in people with AI/ACC.

Healthcare professionals recognized that preventing adrenal
crisis is one of the main goals for patient on AI treatment. 40 AI education is paramount for patients and their caregivers to anticipate, recognize and intervene early to prevent or reduce the occurrence of adrenal crisis. 40,41 Patients with AI related to ACC expressed their frustration that simple flu could lead to hospitalization. 17 Patients with non-ACC related AI who were given AI education and were able to self-inject glucocorticoid during emergency had quicker symptoms improvement and were more likely to get treated in an outpatient setting compared with those who did not self-inject. 42 Similarly, those who experienced adrenal crisis were more likely to adjust their glucocorticoid dose when required compared to those without. 43,44 Patients with AI without ACC who received AI education self-reported that they were better in recognizing signs and symptoms of their adrenal crisis immediately after the training rather than 6-9 months afterwards. 44

| Strengths
This is the first review to identify the burden of disease and treatment on this population, and the paucity of patient experience evidence in the management of AI/ACC. The search terms for AI and ACC had many variations which may have impacted on the search outcomes.

| Limitation
Low-quality evidence such as the case reports were included as

| Recommendations for research and clinical practice
Cancer survivorship is considered to have three phases of survival including dealing with one's own sense of mortality, engaging with a period of surveillance, aiming to lower the risk of recurrence and other risks related to oncology late effects. 35 Healthcare professionals should recognize survivorship phases including side effects and symptoms monitoring to optimize care, just as they might use mitotane levels to optimize patient's progression free survival. In the context of ACC, the development of AI and the shared features of AI such as nausea and tiredness, with the disease and treatment related symptoms, add an additional dimension to the complexity of management. The relative paucity of data indicates a need to evaluate a self-management programme for AI, although acknowledging that the timing of such an intervention would need to align with the phase of survival.
A recognition that adrenal crisis related to AI management in ACC might be a preventable condition is an important understanding for healthcare professionals. The impact of AI/ACC on patient's wellbeing from diseases, medication and therapeutic regimes places a considerable burden on their survivorship.
Clinicians should be alerted to these burdens and the patients' capacity to withstand the burden and concord with treatment recommendations requires careful assessment and supportive care provision. Finally, the relationship between wellbeing and survivorship of ACC warrants further investigation to understand the poor survival of this cohort.

| CON CLUS ION
Patients with AI/ACC face many challenges. Their lived experience remains poorly understood and they are faced with burdens that may impact on their wellbeing from diagnosis and throughout their treatment pathways. Carers of patients' living with ACC play a crucial role in supporting their wellbeing and lived experience; improved structure is required to support carers' efforts. Qualitative interviews are needed to illuminate the lived experience, wellbeing and needs of patients living with this condition. Combining AI and ACC is particularly difficult for patients in terms of the challenges it presents, and the impact of those challenges on their wellbeing. A better understanding of those challenges would enable healthcare professionals to provide much more person-centred and ameliorative care.

CO N FLI C T O F I NTE R E S T
The authors have no financial or non-financial competing interests to declare.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing is not applicable to this article as no new data were created or analyzed in this study.