Introduction

Neuroendocrine tumours (NETs) are a group of complex tumours that arise from specialised cells called neuroendocrine cells, originating from the intestine, pancreas, lung, and other organs. Although there are many types of NETs, they have traditionally been treated as a group because of their common cellular characteristics and clinical behaviour. NETs are relatively rare, with an annual incidence of 2.5–5 cases per 100,000 [1, 2]. However, as the 5-year survival is greater than 60%, the prevalence of NETs is 35/100,000 and these patients are more likely to be encountered in practice than gastric, pancreatic, oesophageal, hepatobiliary adenocarcinomas, or any two of these cancers combined [3].

Some NETs secrete bioactive peptides that may cause a cluster of symptoms described as “carcinoid syndrome”, including flushing, diarrhoea, wheezing, and heart valve damage. These tumours are known as functional NETs. In addition, a very small number of functional NETs secrete specific hormones leading to other recognised clinical presentations, for example gastrinomas and insulinomas. However, most well-differentiated NETs are non-functioning (do not secrete hormones) and may cause nil or minimal symptoms until they become very large or metastatic.

Surgery for localised disease is the only curative treatment available. Many NETs, such as appendiceal and rectal NETs, are usually cured by surgery. However, some people with NETs present with metastatic disease or subsequently develop metastases after resection of localised disease. While metastatic NETs are not curable, the tumours are frequently slowly growing so patients may live for many years. Treatment options include systemic therapies such as somatostatin analogues and chemotherapy, targeted therapies such as everolimus and sunitinib, local therapies such as debulking surgery, hepatic artery embolization, or external beam radiotherapy and selectively available therapies such as peptide receptor radio-therapy (PRRT).

NETs are poorly understood, both by patients and their health-care providers. Due to the rarity, heterogeneity, non-specific symptoms, and unique biology of NETs, patients harbouring these tumours may be confronted with specific problems that are somewhat different from those of patients with more common epithelial cancers. The prognosis for patients with advanced NETs is often uncertain, both clinically and in relation to the ability to plan ahead practically and financially [4]. Qualitative interviews with 30 people living with NETs in Australia describe NETs as atypical, because they are often incurable and slowly progressing, and their treatment is not associated with common side effects, such as hair or weight loss [5]. As a consequence, people with NETs do not typify ‘normal’ cancer sufferers and are vulnerable to being overlooked in the provision of social support and counselling [5]. The carcinoid syndrome, when present, further decreases quality of life [6,7,8]. In addition, NET patients may encounter distinct issues when accessing the health-care system. Self-reported survey data from 1928 NET patients, mostly from North America and Europe, found that about half of patients desired better access to NET specialists (56%) and a better coordinated NET medical team (45%) [9].

Qualitative research suggests that NET patients have unmet needs regarding disease-specific information, treatment centres, and support [10]. However, there have been no quantitative studies that have used validated instruments to assess unmet supportive care needs or perception of care coordination among the population of people living with NETs. Furthermore, while many studies have assessed quality of life outcomes of selected groups of NET patients receiving various treatments, many of these have not been population-based and have had a range of methodological shortcomings [11].

This study used validated assessment tools to assess perceptions of care coordination, identify unmet supportive care needs, and examine personal and clinical factors associated with these outcomes in a group of NET patients treated at a major tertiary hospital in Australia. Given the distinct access issues NET patients have reported facing in other global regions [9], we investigated whether perception of care coordination among Australian NET patients varied by whether they were cared for at a single tertiary hospital with a specific NET management team versus shared care between the tertiary hospital and a specialist at another site. We also quantified the proportion of NET patients experiencing anxiety, depression, and NET-related physical symptoms, and the proportion that had quality of life scores below the general population average.

Methods

Participants and procedures

We conducted a cross-sectional mail survey of people with NETs who were being actively managed by the RBWH NET Multi-Disciplinary Team between August 2016 and February 2017. Patients with a histologically confirmed grade 1 or 2 NET [12], aged over 18 years, proficient in the English language, and able to give informed consent were eligible to participate. Patients with rapidly growing grade 3 NETS, such as small cell carcinoma, were excluded due to their significantly more aggressive clinical behaviour and worse survival [1].

Patients were mailed an information sheet, consent form, and questionnaire and asked to return them in an enclosed reply-paid envelope. If the questionnaire and consent form were not returned within approximately 3 weeks of the package being mailed, the study nurse telephoned the patient to ascertain their willingness to participate. Postcode was used to classify participants’ home location as major city versus regional/remote area using the Accessibility/Remoteness Index of Australia [13]. We obtained clinical data from medical records, including date of initial diagnosis, primary site, functional status, date diagnosed with metastatic disease if applicable, all treatments received, and whether RBWH was the only specialist provider or not.

Patient-reported outcome measures

We administered four different instruments, the Cancer Care Co-ordination Questionnaire (CCCQ), the Supportive Care Needs Survey-Short Form (SCNS-SF34), the Functional Assessment of Cancer Therapy - General (FACT-G), and Hospital Anxiety and Depression Scale (HADS). These are described in detail below.

The CCCQ has 20 items which measure patients’ perception of cancer coordination on two subscales: communication (range 13–65) and navigation (range 7–35) [14]. Together, the subscales can be summed to a total score (range 20–100). These two components explained 91% of the variance. The instrument and its two subscales have high internal consistency (Cronbach’s alpha 0.88, 0.87, and 0.73 respectively). All questions are answered on a 4-point Likert scale (1 to 5). A higher score indicates better care coordination.

The SCNS-SF34 assesses needs across five domains: psychological (10 items); physical/daily living (5 items); health system/information (11 items); patient care/support (5 items); and sexuality (3 items) [15]. This tool asks participants to rate their need for help with each item over the past month on a 5-point scale where 1 = not applicable (no need), 2 = satisfied (need was met), 3 = low unmet need, 4 = moderate unmet need, and 5 = high unmet need. Binary categories for any overall and domain-specific needs can be classified as follows: ‘no-to-low needs’ versus ‘at least one moderate-to-high need’. The SCNS-SF34 is a validated measure; its five domains collectively accounted for 73% of the variance, with Cronbach’s alpha for domains ranging from 0.86 to 0.96 [15].

The FACT-G is a 27-item scale which measures physical (range 0–28), social (range 0–28), emotional (range 0–24), and functional (range 0–28) well-being [16]. Together, the subscales add up to an overall quality of life score (range 0–108). A higher score indicates better quality of life. All scales have good-to-excellent reliability [16]. As there was no NET-specific subscale of the FACT instrument suite, we used 15 NET-specific physical symptom items from the European Organization for Research and Treatment Quality of Life Questionnaire GastroIntestinal NeuroEndocrine Tumours subscale (EORTC QLQ-GINET21) [17] to measure cancer-specific symptoms. For consistency, the FACT 5-point response scale was used for the 15 NET-specific symptoms.

The HADS assesses psychological distress [18]. It has been validated against clinical interview, and its sensitivity and specificity for depression and anxiety in cancer patients is good-to-excellent [19, 20]. All questions are answered on a 4-point Likert scale (0 to 3). Seven items form a depression scale and seven an anxiety scale (both scales range from 0 to 21). A score of 8–10 in each subscale indicates borderline depression or anxiety, while a score of 11 or greater indicates a likely state of depression or anxiety.

Statistical methods

To rank the 20 care coordination items in order of how they were rated by participants, we calculated the mean score for each item. We assessed associations between personal and clinical factors with the overall care coordination score using the two-sample t test and analysis of variance. We also used the Mann-Whitney tests to assess differences in each care coordination item according to whether RBWH was the only specialist provider or not. We considered differences with p < 0.05 to be statistically significant.

We calculated the proportion of participants who reported a moderate-to-high level need for each supportive care need item and each domain and the proportion of participants classified as having normal, borderline, and clinical anxiety and depression. Mean scores for anxiety, depression, quality of life, and well-being subscales were also calculated. The well-being subscale scores and overall quality of life were compared to Australian norms [21]. Finally, we classified each of the NET-specific symptoms as not at all to somewhat versus quite a bit to very much and calculated the proportion in the latter category.

Results

Participant response and characteristics

In total, 170 eligible patients were invited to participate in the study and 111 responded (65% response proportion). Of the non-responders, 6 (4%) could not be contacted, 7 (4%) died shortly after receiving the questionnaire, and 46 (27%) did not return the questionnaire. The demographic and clinical characteristics of participants are shown in Table 1. Most (61%) were 60 years or older, 56% were male, 76% were married or living with their partner, 67% had completed further education after high school, 55% lived in a major city, and 45% were treated solely at RBWH. Two-thirds (66%) of participants had metastatic disease at the time of initial NET diagnosis, and 93% had metastatic disease at the time of survey completion. The time since initial diagnosis ranged from 2 months to 27 years with the majority of primary tumours originating from the small bowel (42%) and pancreas (27%). Approximately half (56%) the tumours were functional. Participants were mostly treated with surgery of the primary tumour (70%), hormone therapy (72%), and PRRT (46%). Live non-responders had similar age (54%; 28/52 aged 60 and over) and sex (54%; 28/52 male) distributions to participants in the study.

Table 1 Participant characteristics (n = 111)
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Care coordination scores

Overall, the mean total cancer care coordination score was 73.7 (11.5 SD), and mean scores for the communication and navigation domains were 47.8 (8.4 SD) and 25.9 (3.9 SD) respectively. The lowest-ranked care items related to health professionals being fully informed about patient history and progress, communication about financial entitlements, and doctors asking about how well the family and patient were coping (Table 2). The number of specialist providers, age, sex, remoteness of home location, time post-diagnosis, tumour functional status, and treatment with PRRT were not significantly associated with total cancer care coordination score (data not shown). However, compared to patients treated solely at RBWH, patients with multiple specialist providers had significantly poorer scores related to health professionals being fully informed about their history and progress and meeting health-care costs (Table 2). Specialist provider type (single/multiple) was not significantly associated with home location (city/regional-remote); thus, these associations were independent of the remoteness of participants’ home location.

Table 2 Care coordination items – ranked from worst (1) to best (20) – reported by people living with neuroendocrine tumours
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Supportive care needs

Sixty-three percent (95% CI 54–72%) of participants reported having at least one moderate-to-high level unmet need. Moderate-to-high level needs were reported by 44% (95% CI 35–54%) of participants for psychological needs, 38% (95% CI 29–47%) for physical/daily living needs, 28% (95% CI 20–37%) for health system/information needs, 17% (95% CI 10–24%) for sexuality needs, and 11% (95% CI 5–17%) for patient care/support needs. The top 10 moderate-to-high unmet need items all came from the physical and psychological domains and are shown in Table 3. Specifically, having a moderate-to-high need for help with lack of energy/tiredness was reported by one in three participants, while about a quarter of participants had a moderate-to-high need for help with their fears about the cancer spreading, their concerns about the worries of those close to them, their uncertainty about the future, and with not being able to do the things they used to do.

Table 3 Top 10 moderate-to-high unmet supportive care needs in 111 people living with neuroendocrine tumours
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Anxiety, depression, quality of life, and cancer-specific symptoms

Overall, 14% (95% CI 8–20%) of participants were classified by the HADS as having clinical anxiety, with an additional 16% (95% CI 9–23%) classified as having borderline anxiety. Nine percent (95% CI 4–14%) of participants were classified as having clinical depression and 11% (95% CI 5–17%) were borderline. Mean scores for anxiety, depression, individual well-being scales, and overall quality of life are shown in Table 4. Compared with the general population average, the majority of people living with NETs reported having lower physical (72%; n = 78) and emotional (72%; n = 79) well-being. The most prevalent symptoms included diarrhoea (29%; 95% CI 21–38%), a bloated feeling in the abdomen (29%; 95% CI 20–38%), abdominal discomfort (27%; 95% CI 18–35%), hot flushes (22%; 95% CI 14–30%), and flatulence (20%; 95% CI 13–28%) (Table 5).

Table 4 Mean anxiety, depression and quality of life scores among 111 people living with neuroendocrine tumours
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Table 5 Gastrointestinal symptoms among 111 people living with neuroendocrine tumours
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Discussion

People with slow-growing metastatic NETs are different to patients with the more common epithelial metastatic cancers. Many of them live with metastatic disease for a long time, yet because NETs are rare, there is little knowledge available about how patients perceive their encounters with the health system and how well their supportive care needs are being met. We found that people with NETs who were seen at a NET specialist centre were satisfied with their knowledge about suitable treatments, the treatments and follow-up planned for them, why they were having treatment, the benefits and harms of treatment, waiting times, who to contact if they had concerns, and access to their general practitioner. In contrast, they were less satisfied with aspects of their care such as health professionals having a full case history, providing information about financial entitlements, and asking about how well they and their family were coping. People who were being managed by multiple specialist providers were significantly less satisfied with health professionals being fully informed about their history and about being able to meet their health-care costs than those solely being managed by specialists at the RBWH. We also found that about one in three people living with NETs reported a moderate-to-high level unmet need for help with fatigue and one in four with psychological concerns about the cancer spreading, uncertainty about the future, and about the worries of those close to them. As the aim of treatment in patients who present with metastatic disease is to improve quality of life rather than achieve a cure [22] and perception of care coordination and unmet supportive care needs are associated with quality of life [23, 24], these are important findings which can be used to guide improvements in practice.

There are few studies of peoples’ cancer care coordination experiences with which to compare our results; most did not use the same instrument or did not report on individual care coordination items [25,26,27,28]. However, one key issue was less satisfaction with health professional asking about how well they and their family were coping [23]. This finding alongside the prevalent concerns of NET patients about the worries of those close to them points to the requirement for more focused awareness of health professional on emotional care of both the patient and their families, especially as these patients often look well and therefore may not be offered support in these areas as often as other patients who look less well [5]. Additionally, our study suggests continuity of care with knowledge of case history could be improved, particularly for patients being cared for by multiple specialist providers. Provision of care plans to patients and all of their providers may be particularly helpful in models of shared care for NET patients.

Patients also expressed a desire for their health professionals to initiate conversations about out-of-pocket expenses and information about financial benefits available, with this being particularly prevalent in patients not being treated solely at the RBWH. This is likely due to RBWH being a public hospital so those treated solely at RBWH have fewer out-of-pocket health-care costs. Some of those treated at multiple institutions likely have a mix of care in the public and private systems, with contingent out-of-pocket costs. Financial uncertainty is likely to be more prevalent in NET patients than in other cancer patient groups given the advanced slow-growing nature of most of these tumours. A German study found that 78% of NET patients reported high out-of-pocket costs, mostly in terms of travel expenses and co-payments for medication and 29% of participants in the study reported a loss of income; 62% of these said this could not be compensated by their savings or credits [29]. Furthermore, higher cancer-related out-of-pocket costs per month were associated with significantly lower quality of life, self-reported health status, and a more severe perception of disease burden [29] indicating the importance of considering targeted measures that could prevent financial problems and reduce emotional burden.

Similarly to many other cancer populations, the top unmet supportive care needs in this study related to fatigue and fear of cancer spreading [30, 31]. The proportion of NET patients reporting these top two needs at moderate-to-high levels was generally similar to or higher than patients with other types of advanced or metastatic cancers. For example, having an unmet need for help with fatigue was reported by 33% of NET patients compared with 28% of people with pancreatic cancer [32], 16–19% of women with ovarian cancer [33], 13% of people with advanced or metastatic prostate cancer [34], < 25% with metastatic breast cancer [35], and 26–30% among people with a mix of different cancer types [36, 37]. Having an unmet need for help with fear of cancer spreading was reported by 26% of NET patients compared with 26% of people with pancreatic cancer [32], 16–25% of women with ovarian cancer [33], 16% of people with advanced or metastatic prostate cancer [34], 33% with metastatic breast cancer [35], and 19% among people with a mix of different cancer types [37]. It is not surprising that we also found people living with NETs to have clinically lower physical and emotional well-being than the general populations. In particular, the proportion with clinical depression (9%) was three times higher than is observed in the general population (3%) [38] and 1.5-fold higher than observed across cancer populations (6%) [39]. In addition to facing one’s own mortality and experiencing existential distress (i.e. concerns about the cancer spreading, uncertainty about the future), depression in this population may be compounded by the high symptom burden and potential social isolation related to one in four participants experiencing frequent to constant diarrhoea, abdominal symptoms, and flushing. These findings emphasise the importance of careful management of physical and psychological symptoms in patients with NETs.

This study adds valuable information to our understanding of patient-reported outcomes in people with NET. It does, however, have several limitations. Participants were recruited from a single treatment centre. While this centre is a specialist centre for NETs and the only treatment centre in Queensland, Australia, to offer PRRT, not all NET patients from Queensland are referred to the RBWH. The sample over-represents patients with metastatic disease, particularly those who are progressing on initial therapy, as well as those receiving PRRT. Furthermore, due to the rarity of the disease, the sample size was relatively small and therefore confidence intervals around point estimates are wide. For practical purposes, the study design was cross-sectional and does not have a sample size that allows for consideration of outcomes during particular events, for example immediately after treatment or during follow-up treatments where supportive care needs are often at their highest. Thus, it is likely that unmet needs may be even higher than reported here at certain times across the care continuum.

Management of people with NETs is complex. With two-thirds of patients in our sample presenting with metastatic disease and one-third living with metastatic disease for more than 5 years, NETs are experienced as a chronic illness, with consequent demands for ongoing coordinated care and high levels of supportive care needs. Internationally, there has been a move toward development of better models of person-centred cancer care to optimise survival times and quality of life [40]. This study identifies key aspects of care that could be improved, including the need for communication of case history between professionals, for health professionals to ask patients and their families about how they are coping, and initiating financial discussions. Enhancing these aspects of care, along with ongoing psychological and physical symptom management, is likely to help with improved perceptions of care provision and patient outcomes for people living with this rare, chronic, and advanced disease.