Quality of care and quality of life as experienced by patients with advanced cancer of a rare tumour type: results of the multicentre observational eQuiPe study

Patients with a rare cancer face difficulties during their disease trajectory, such as delayed diagnosis and lack of expert care. However, little is known about their perceived quality of care (QoC) and quality of life (QoL) in the advanced disease stage. We aimed to assess the QoC and QoL as experienced by patients with advanced rare cancers compared to patients with advanced common cancers. In this cross-sectional study, baseline data of patients with advanced cancer from the multicentre, longitudinal, observational eQuipe study were analysed. Multivariable linear regression analyses were conducted to assess differences in experienced QoC (continuity of care, continuity of information, and satisfaction with care) and QoL (functioning, symptoms, overall QoL, and social wellbeing) between advanced rare and common cancer patients. Of the 1087 included patients, 106 (9.8%) had a rare cancer type. In comparison to patients with advanced common cancers, patients with advanced rare cancers experienced significantly lower continuity of care (77.8 vs. 71.1 respectively, p = 0.011) and social functioning (78.8 vs. 72.6 respectively, p = 0.012). No differences were found regarding continuity of information, satisfaction with care, overall QoL, and social wellbeing. Patients with advanced rare cancers experience less continuity of care, and the impact of the disease on social and family life seems higher compared to patients with advanced common cancers. To enhance the QoC and QoL of patients with advanced rare cancers, supportive care should mainly focus on improving continuity of care and patients’ social functioning.


Introduction
In Europe, 3.9 million cancer diagnoses are made every year [1], of which 24% are rare cancers [2]. As defined by the Surveillance of Rare Cancers in Europe (RARECARE), rare cancers are those occurring in fewer than 6 per 100,000 people per year [3]. The five-year survival rate of patients with a rare tumour type is about 17% lower compared to patients with a common tumour type (52.0% vs. 68.7%, respectively) [4]. This difference in survival can partly be explained by the fact that rare cancer patients are more frequently diagnosed in an incurable, advanced stage of their disease [5,6]. Due to their rarity, there is a lack of clinical expertise, causing rare cancers to be associated with delayed, and sometimes even incorrect, diagnosis [7][8][9]. Moreover, the diagnosis rare cancer can bring increased burden for patients compared to more common cancers, due to several difficulties in the treatment phase of the disease [9]. First, trustworthy clinical trials with small patient populations are difficult to conduct and to fund, hindering the development of effective treatments and guidelines for rare cancers [9]. Second, the absence of expert care and adequate information regarding rare cancers can lead to more uncertainty among patients with this type of cancer [9][10][11].
Due to the delayed and inconclusive diagnostic and treatment processes and the lack of expertise, patients with advanced rare cancer may have poorer healthcare experiences compared to advanced common cancer patients [12,13]. Their perceived Quality of Care (QoC), conceptualized as the access to and effectiveness of care [14], may therefore be limited. Patients with advanced cancer experience problems in the coordination of care by different healthcare professionals, as well as problems regarding the adjustment of care to one's personal situation, quick responses to acute problems, information giving, and emotional support [15]. An important aspect of QoC, according to advanced cancer patients, is the organization of end-of-life care [15,16]. To enhance the quality of treatment and care for patients with rare cancers, they are more often than patients with common cancers treated in a different hospital from where they were diagnosed [17]. This situation may lead to more fragmentation, making it challenging to determine who is in charge of the provided care [18,19]. Continuity of care, conceptualized as healthcare that is connected, coherent and consistent with a patient's healthcare needs and personal situation [20], may therefore be limited [16,21].
Satisfaction with care is positively associated with quality of life (QoL) in patients with advanced cancer [22,23]. The challenges and uncertainty regarding care and treatment faced by rare cancer patients may, therefore, also lead to impairments in their perceived QoL. A recent study showed that the QoL of patients with a rare disease is lower compared to that of patients with a common disease, probably due to poor diagnosis, treatment, information, and psychosocial support processes [24]. Furthermore, it was previously shown by Robinson et al. that diagnostic delays are associated with reduced QoL and specifically with reduced functioning in daily and social life [25]. Difficulties in continuing their life as it was are also frequently mentioned by patients with advanced cancer [26,27]. Moreover, advanced cancer patients often feel socially excluded, because their medical appointments and the physical and psychological symptoms related to advanced cancer and its treatments make them miss out on social events [27]. Even though cancer treatment in the palliative phase predominantly focuses on reducing symptoms and enhancing a patient's functioning, the experienced QoL of advanced cancer patients is impaired compared to non-advanced cancer patients [28,29].
Currently, little is known about the experienced QoC and QoL of rare cancer patients who are in the advanced stage of their disease, as previous studies mostly focussed on individual types of rare cancer, or did not focus specifically on the advanced disease stage. Combining the difficulties in care and QoL seen in both advanced and rare cancer patients, we hypothesized that patients with advanced rare cancer experience a worse QoC and QoL compared to patients with advanced common cancer. Insights in advanced rare cancer patients' experiences may provide information about whether there is room for improvement in the care and support for this specific patient group and about the aspects of care and QoL which are lacking. Therefore, this study aimed to assess the experienced QoC and QoL in advanced cancer patients with a rare tumour type compared to advanced cancer patients with a common tumour type.

Study design
A cross-sectional study was conducted, using baseline patient data from the prospective, multicentre, observational study eQuiPe. In the eQuiPe study, data has been collected on the experienced QoC and QoL of advanced cancer patients, both rare and common, and their relatives. Clinical data on the typology and morphology of the primary tumour was obtained from the Netherlands Cancer Registry (NCR) and linked to the baseline patient data of the eQuiPe study.

Setting and study population
Patients in eQuiPe were recruited via their treating physician in one of the 40 participating hospitals in the Netherlands, with a broad representation of academic, top-clinical, and general hospitals. Advanced cancer patients also had the possibility of self-enrolment via a Dutch online platform for patients with cancer and their relatives (www. kanker. nl). Baseline data on the experienced QoC and QoL was collected between November 2017 and March 2020.
All adult patients (≥ 18 years) with a diagnosis of a metastatic solid tumour (stage IV) were eligible for participation. Additional inclusion criteria were formulated for patients with breast and prostate cancer to limit overrepresentation of patients with advanced cancer who had a relatively good prognosis. Patients with breast cancer were eligible when diagnosed with a primary tumour in stage IV 1 3 and metastases in multiple organ systems. Patients diagnosed with prostate cancer in stage IV were eligible when their cancer was castrate-resistant. Patients were excluded from participation if they had a history of severe psychiatric illness, suffered from dementia, or were not able to complete a self-reported Dutch questionnaire. Patients were classified as having a rare or common cancer based on the typology and morphology of the patient's tumour and the updated version (February 2019) of the RARE-CARENet cancer list [4,30].

Data collection
Potentially eligible patients received an information letter on the study from their physician, who asked them if the research team may contact them. Patients who enrolled themselves provided their contact information via the online platform. The researchers approached all patients by phone, discussing participation. Patients who agreed to participate were asked to sign an informed consent form and to complete a questionnaire regarding QoC and QoL every 3 months until the death of the patient or a wish to withdraw. The informed consent form and the questionnaire could be completed on paper or online via the Patient Reported Outcomes Following Initial treatment and Long-term Evaluation of Survivorship (PROFILES) registry. More details on the eQuiPe study can be found in the study protocol [31].

Experienced quality of care
Since there is no established definition of quality of care, patients with advanced cancer were asked to share their perspectives on essential aspects of quality of care in focus groups and interviews prior to the cohort study. Identified themes were subsequently captured in the cohort study by means of various "quality of care" questionnaires. Continuity of care and continuity of information from different healthcare professionals, as part of QoC, were measured using two items of the Consumer Quality Index Palliative Care (CQ-index PC) [32]. Satisfaction with care was measured using items from the satisfaction with in-patient cancer care questionnaire (IN-PATSAT32) [33] and an additional self-developed item regarding the emphatic skills of healthcare professionals. All items were measured on a 5-point Likert scale ranging from "poor" to "excellent" and referred to the past month. Scores were linearly transformed to a score between 0 and 100. A higher score indicated a higher level of satisfaction with care or better continuity of care and information [33].

Experienced quality of life
QoL was measured by the well-validated European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) [34]. The EORTC QLQ-C30 contains five functioning scales (i.e. emotional, social, physical, role, and cognitive functioning), three symptom scales (i.e. fatigue, nausea, and pain), a global QoL scale, as well as six single items (i.e. dyspnoea, insomnia, appetite loss, constipation, diarrhoea, and financial impact), relating to the situation of the past week [34]. The questionnaire uses a 7-point response format for the global QoL, ranging from "very poor" to "excellent", and a 4-point response format for all other items, ranging from "not at all" to "very much." All scores were linearly transformed to a score between 0 and 100. A higher score indicated greater global QoL, a higher functioning level, a higher symptom burden, or a greater financial impact [34,35].
The summary QoL score as developed by Giesinger was used, as the mean of the functioning and symptom items and scales [36]. This summary score is better than the global QoL score at detecting differences between clinically different patient groups and has an equal or higher validity than the underlying scale scores in patients with cancer [36,37]. The higher the summary score, the higher the experienced QoL.
Social support and relationships were additionally assessed by the social/family wellbeing subscale of the Functional Assessment of Cancer Therapy -General (FACT-G) [38], as these aspects play a key role in a person's sense of wellbeing [34] and were not extensively measured in the EORTC QLQ-C30 [39]. These items were measured over the past week on a 5-point scale ranging from "not at all" to "very much." A summary variable with a 0-24 scale was created by adding up the scores from each item, with a higher score indicating a higher level of social wellbeing [38].

Sociodemographic and clinical data
Age, gender, marital status, education, and ethnicity were self-reported. Education was categorized into low, medium, and high according to the International Standard Classification of Education guidelines [40]. Time since primary diagnosis was obtained by calculating the difference in days between the date the questionnaire was completed and the date of primary diagnosis as extracted from the NCR.

Statistical analysis
Descriptive statistics were used to examine the sociodemographic and clinical characteristics and the perceived QoC and QoL of advanced cancer patients with a rare or common tumour type. Univariable linear regression analyses were performed on both the main and additional QoC and QoL outcomes. An adjustment was made for age and gender in multivariable linear regression analyses. When age was not linearly related to the outcome, it was taken into account as categorical variable (18-50, 50-75, 75 + years) [29]. Missing data in the subscales of QoC and QoL ranged between 0.9 and 7.5% and were found to be completely missing at random. The application of multiple imputation prior to the linear regression analyses did not affect the results of the analyses, when compared to the analyses without multiple imputation of the missing values. Therefore, this technique was not used in the final analyses. Statistical analyses were performed using statistical packages STATA version 16. A two-sided p-value < 0.05 was considered statistically significant.

Results
In total, 1695 patients with advanced cancer were contacted by phone. Of them, 255 (15%) patients declined to participate, 337 (20%) patients dropped out after enrolment, and 16 (1%) patients were excluded, because there was no data available on their tumour type or they had both a rare and a common tumour type. A total of 1087 patients were eligible for analysis, of which 106 patients (9.8%) had a rare tumour type and 981 patients (90.2%) had a common tumour type (Fig. 1).

Socio-demographic and clinical characteristics
Both patients with advanced rare cancer and patients with advanced common cancer were on average 65 years old. Most patients with a rare tumour type were female (57%), and in the group of patients with a common tumour type, 48% were female. Most patients with rare cancer were diagnosed with a tumour of the female genital organs (23%), digestive tract (23%), thorax (12%), or neuroendocrine system (11%) ( Table 1).
With regard to QoC, both patients with advanced rare cancer as patients with advanced common cancer scored relatively high on continuity of information (90.8 and 89.6, respectively). Lower mean scores were found regarding continuity of care (71.1 and 77.8, respectively), in disadvantage of patients with rare cancers. Regarding QoL, both patient groups scored relatively low on role functioning. Patients with advanced rare cancers had a slightly worse mean score for social functioning (difference 6.3 points) ( Table 2).

Experienced quality of care
Patients with advanced rare cancer experienced a significantly lower continuity of care (β = − 6.411, p = 0.011) than patients with advanced common cancer, adjusted for age and gender. There were no significant differences between the patient groups regarding continuity of information from different healthcare professionals, general satisfaction with and availability of care, information provision, and the empathic, technical, and interpersonal skills of healthcare professionals (Table 3).

Experienced quality of life
Patients with advanced rare cancer experienced a lower social functioning compared to patients with advanced common cancer, adjusted for age and gender (β = − 6.314, p = 0.012). Advanced rare and advanced common cancer patients did not differ significantly regarding the QoL summary score; global QoL; emotional, physical, role, and cognitive functioning; all symptom scales; and social support and relationships (Table 3).

Main findings
This study shows that advanced rare cancer patients experience a lower continuity of care and social functioning compared to patients with advanced common cancer. No different experiences were found between rare and common cancer patients in the advance disease stage regarding experienced continuity of information, satisfaction with care, overall QoL, and social wellbeing.

Interpretation of findings
Several findings deserve particular attention. First, patients with advanced rare cancer especially experience a lower level of continuity of care, compared to patients with advanced common cancer. A low continuity of care, in this study, refers to disconnected care from different healthcare professionals. Coordination of care seems difficult to guarantee when multiple healthcare professionals are involved in a patient's care [15,41,42]. In a previous study, patients with advanced cancer highlighted the importance of clear procedures and proper information transfer between healthcare professionals for quality palliative care; however, these requirements were often not met [42]. Rare cancer patients are more commonly referred to other specialists for diagnosis and treatment than common cancer patients, possibly explaining the difference in experienced continuity of care 1 3 between these patient groups [18,43]. Moreover, a metasummary by Haggerty et al. showed that discontinuity in care as experienced by patients is higher when trust or clarity in the pathway of care is lacking [44]. Remarkably, the perceived continuity of information was high in both groups and did not differ. The question "Do your healthcare providers give you contradictory information?" may have been too specific to examine the concept of information continuity, which also entails communicating a patient's information to other healthcare professionals and sharing information with the patient on a timely basis [45].
Second, the fact that the level of social functioning was statistically significantly lower in advanced rare cancer patients compared to the advanced common cancer patients, while this difference could not be found for social wellbeing, may be explained by differences in content of both measures. Social functioning from the EORTC QLQ-C30 refers to the impact of the disease on family life and social activities, whereas social wellbeing from the FACT-G refers to relationships with and social support from relatives [39]. Because of a more intense diagnosis trajectory and longer travel distances to receive specialized care and treatment [7,9,17], rare cancer patients may have to miss out on social events more frequently than common cancer patients, resulting in a lower level of social functioning. With regard to social wellbeing, the percentage of rare cancer patients who feel supported and understood by their relatives is equal to that of common cancer patients, according to a poll concerning adult Dutch cancer patients [46]. Third, contrary to our expectations, no statistically significant difference was found in overall experienced QoL between advanced rare and advanced common cancer patients. Previously, Rodriguez et al. found that social functioning is one of the most important contributors to QoL among advanced cancer patients: more important than psychical and psychological functioning or any of the symptoms from the EORTC QLQ-C30 [47]. However, when calculating the summary QoL score, all functioning and symptom scales are weighted equally. As a result, the effect of social functioning on perceived QoL disappears in the summary QoL score. Another explanation could be that differences  (17) 322 (33) in the disease trajectory between patients with rare cancer and patients with common cancer may be less prevalent when the disease has reached the advanced stage. In this advanced disease stage, the care for both patient groups is less disease-specific and mainly focussed on reducing symptoms and improving a patient's performance. For both rare and common cancer patients, this palliative phase can be experienced as frightening with an uncertain prognosis and high symptom burden [41]. Lastly, both rare and common cancer patients in the current study score relatively high on all scales, except for physical and cognitive functioning, and diarrhoea [48]. This is also true regarding satisfaction with care [23] and may be explained by the remaining survival time of the patient population. The current analyses were performed on baseline data from patients expected to be in their last year of life. Previous studies showed that patients who are less close to death generally are more satisfied with care and experience a higher QoL [15,49]. Since the QoL values in our study were comparable to the QoL values previously found in Dutch cancer patients with 9-12 months to live [49], the relatively high QoC and QoL values in the current study may be accurate for advanced cancer patients who reached their last year of life.

Strengths and limitations
To the best of our knowledge, this is the first study among advanced cancer patients to assess the experienced QoC and QoL of patients with a rare cancer compared to patients with a common cancer. This study is further strengthened by using (items from) validated questionnaires, tailored to the aspects of healthcare that advanced rare cancer patients find most important [16,31]. Moreover, it involves a cancer population from 40 different hospitals throughout the Netherlands, which enhances the generalizability of the results.
This study also has several limitations that need to be addressed. First, the eQuiPe study was not specifically designed to compare QoC and QoL outcomes of rare cancer patients to that of common cancer patients in the advanced disease stage. Therefore, the distribution of tumour types within both the rare cancer group and the common cancer group is not entirely representative of the Dutch cancer population [4,11], reducing the generalizability of the results from this study. When interpreting our results to international contexts, differences in the healthcare system should be taken into account as the centralisation pattern and treatment volumes in the Netherlands are high when compared to other European countries [1]. Second, analysing multiple outcomes of QoC and QoL comes with a greater risk of type-1 errors as a result of multiple testing [36]. Therefore, conclusions regarding the additional QoC and QoL outcomes should be taken with caution. However, since this study was a first exploratory study in this field, no a priori selection was made regarding QoC and QoL outcomes.
Lastly, since patients in this study were mainly recruited by their own physicians, it is likely that selection bias is present when mostly patients in relatively good health and satisfied with care were asked to participate. Moreover, in self-reported questionnaires with a sensitive or private subject, social desirability bias is a common issue [50,51]. Even though the recruiting physicians were not the ones receiving the answers to the questionnaire, patients may have felt like they should give positive answers, because they are grateful or scared that their information would be revealed [32]. The relatively high scores in both groups may have led to an underestimation of the differences in perceived QoC and QoL between advanced rare and advanced common cancer patients. Missing values were between 5 and 7.5% for the subscales of continuity of information, continuity of care, and emphatical skills of healthcare professionals. As multiple imputation of these values did not influence the results of the analyses, it is not expected any bias was caused.

Implications for practice and research
Minimal clinical important differences should be taken into account. Although a statistical significant difference was found between advanced rare and common cancer patients regarding social functioning, this difference did not reach the minimal important difference of meaningful  [52]. However, based on the guidelines of Cocks et al. for interpreting cross-sectional differences in QoL scores, the small difference in social functioning refers to a subtle but clinically relevant difference [53]. Even though differences are small and no consensus is reached on minimal clinical important differences in previous literature, healthcare professionals should be more aware of their approach with and communication to advanced rare cancer patients and the effect on the patient's social and family life.
To enhance the continuity of care for rare cancer patients in the advanced disease stage, the organization of their endof-life care should be reconsidered. Enhancing the continuity of care for cancer patients leads to less demand for supportive care in the future and can improve a patient's QoL [54][55][56]. Therefore, communication methods between different healthcare professionals involved should be improved. A central point of care close to their homes might be beneficial to coordinate the patient's care pathway and the integration of palliative care for patients with an advanced rare cancer. Advanced cancer patients have previously expressed a need for a case manager who is aware of their personal and medical situation and who can acts as a liaison between different healthcare professionals [16,57]. Other options, to provide care that is more connected and less fragmented, are centralization of care or organizing care according to the hub and spoke model [17,58]. Centralization is one of the focus points in the recently published Integral Care Agreement of the Dutch Ministry of Health, Welfare and Sport. This can particularly be beneficial for rare cancer patients, because the aim in healthcare is to concentrate the level of expertise in one specific place and herewith improve disease outcomes; however, travel times for patients may rise [17]. The hub and spoke model is a specific way of centralizing care, in which the spoke is the local hospital for the patient and the hub is a specialized hospital in which more complex care and treatments are given and from which expert advice can be obtained [58]. These interventions may be effective for patients with a rare tumour type, as these patients typically have a less paved care pathway within the healthcare system and are less likely to receive appropriate information [59]. Therefore, they may be more in need of a central person or point of care, compared to the overall cancer population. Future research is needed that focuses on the effectiveness of before mentioned methods to improve continuity of care, as well as a study that assesses the components of continuity of care that are lacking in patients with advanced rare cancer.
A qualitative follow-up study concerning patients with advanced rare cancer is recommended to identify underlying causes that may explain the reduced level of social functioning. Further, a longitudinal study on the experienced QoC and QoL of advanced rare and advanced common cancer patients might be valuable in determining whether the differences found in the current study are stable over time and whether time until death affects the current findings. When sample sizes are increased, subgroup analyses may reveal which rare tumour types are related to the most issues in QoC and QoL.

Conclusion
Our findings suggest that patients with an advanced rare cancer may benefit from supportive care systems enhancing the continuity of care and the possibilities to maintain their social and family life within palliative care. This knowledge can be used as input to improve the experienced QoC and QoL of patients with advanced rare cancer and thereby reduce the impact of having a rare cancer.