Palliative Care Outpatients in a German Comprehensive Cancer Center - Identifying Indicators for Early and Late Referral

Abstract

Background.

Despite that early integration of palliative care is recommended in advanced cancer patients, referrals to specialisedana palliative care (SPC) frequently occur late. Well-defined referral criteria are still missing. We analyzed indicators associated with early (ERs) and late referral (LRs) to SPC of a high volume outpatient unit of a German comprehensive cancer center.

Methods.

Characteristics, laboratory parameters and symptom burden of 281 patients at first SPC referral were analyzed. Timing of referral was categorized as early, intermediate and late (> 12, 3–12 and < 3 months before death). Ordinal logistic regression analyze was used to find factors related to referral timing. Kruskal-Wallis test was used to determine symptom severity and laboratory parameter in each referral category.

Results.

LRs (50.7%) had worse scores of weakness, loss of appetite, drowsiness, assistance of daily living (all p < 0.001) and organisation of care (p < 0.01) in contrast to ERs. The mean symptom sum score was significantly higher in LRs than ERs (13.03 vs. 16.08; p < 0.01). Parameters indicative of poor prognosis, such as elevated LDH, CRP and neutrophil-to-lymphocyte ratio (NLR) (p < 0.01) as well as the presence of ascites (p < 0.05), were significantly higher (all p < 0.001) in LRs. In univariable analyzes, psychological distress (p < 0.05) and female gender (p < 0.05) were independently associated with an ER.

Conclusion.

A symptom sum score and parameters of poor prognosis like NLR or LDH might be useful to integrate into palliative care screening tools.

1. Background

Advanced cancer patients should be offered palliative care treatment timely in combination with oncological cancer therapy (1, 2). Multiple studies have shown that integration of palliative care improves various modalities of patients’ environment, such as quality of life, patient experience, patient and family satisfaction, symptom burden and in the form of less aggressive care at the end of life (3–5).

Various conceptual frameworks have been proposed including a recent Delphi study from Hui et al. (6) involving 60 international experts supporting a combination of trigger-based and clinician-based approaches to timely offer palliative care referral, but not all of them are consistently used (7–9). A large retrospective cohort study with more than 22,500 patients could demonstrate that outpatients had high scores in the Edmonton Symptom Assessment System (ESAS) for tiredness, lack of appetite and impaired wellbeing (10). Another study also mentioned symptoms like lack of appetite, drowsiness, dyspnoea and fatigue as significant factors that tend to intensify in outpatients at the end of life (11). Additionally, differences in gender and cancer subtypes were observed regarding palliative care consultations (12).

Due to the ongoing process of improving treatment options for advanced cancer patients, cancer is increasingly becoming a kind of "chronic disease" with a prolonged survival time (13). In this context, outpatient care and treatment options such as specialised palliative care are increasingly coming to the fore (14). Therefore, many oncological comprehensive cancer centres (CCC) integrate nowadays a specialised palliative care consultation (SPCC) for outpatients into their routine care (15, 16).

One of these CCC in Germany established a SPCC in a high volume outpatient clinic for cancer patients (17). In a former study, we used a patient reported outcome measurement called MInimal DOcumentation System (MIDOS) in the oncological outpatient setting. We showed that the symptoms “weakness”, “depression” and “anxiety” were predictive factors for patient's request of receiving a SPCC (18).

Additionally, laboratory parameter are nowadays not integrated in PC routine screening tools, which are frequently used (6, 19). Therefore, we wanted to explore the contribution of laboratory parameters as indicators in cancer patients regarding SPCC. Our study analyzes the symptom burden as well as laboratory data at first referral to an outpatient SPCC. Our objective is to analyzes common clinical and laboratory indicators in early and late referrals to an SPCC. Secondary, we describe symptom burden using the validated Hospice and Palliative Care Evaluation (HOPE) Symptoms and Problem Checklist, which is a common tool used in German specialized palliative care units (20).

Although many referral criteria and clinical indicators have been already described, the role of laboratory parameters as indicators of early referral remains unexamined. Furthermore, current studies of different cancer types showed that the neutrophil-to-lymphocyte ratio (NLR) is a predictor for reduced overall survival in cancer patients. Therefore, we wanted to analyze symptom burden, clinical indicators and timing of referral to a SPCC in our patient population and explore the role of NLR as a laboratory indicator. Moreover, we hypothesized that the symptom burden would be lower in early referrals and patients who were female and had gynaecological cancer types would be referred earlier to a SPCC, similar to other studies.

2. Methods

3. Results

From November 2013 to December 2020, a total of 310 patients were referred to an outpatient SPCC. Of these, two patients died before the first presentation and 27 patients did not undergo a palliative care consultation for various reasons. Thus, 281 patients underwent a SPCC. Up to the evaluation period on 20 March 2021, 227 patients had died.

The median age of all patients at first presentation in the SPCC was 62 (18–88) years. Gastrointestinal (N = 72; 25.6%), lung (N = 62; 22.1%), breast cancer (N = 49; 17.4%) and sarcomas (N = 41; 14.6%) were the most common tumour entities among our cohort. At first referral, 189 patients (67.3%) were receiving chemotherapy at the time. The majority of patients were in the first (N = 74; 26.3%) and second (N = 73; 26%) palliative chemotherapy line. The median time from first referral to death was 6.38 months (± 9.02). Cumulatively, 95.2% of patients died within two years after the initial presentation. Detailed demographic information is shown in Table 1.

As shown in Table 2, almost 60 percent of patients did not have a qualified social care planning at time of referral. Before initial presentation, 81.7 percent of patients already received pain medication. Most patients were referred late (n = 115; 50.7%), 82 (36.1%) patients were referred intermediate and 30 (13.2%) patients were referred early. Patients who were referred early to palliative care were more likely to have breast cancer (40.0% referred early vs. 3.3–20.0% for other cancer sites) and the reason of referral was mostly related to social care planning (n = 6; 20.0%) and psychological distress (n = 6; 20.0%). Patients with a late referral presented worse physical condition in terms of ECOG performance status (H = 30.054, p < 0.001, n = 226).

The single factor variance analyzes showed that most of patients who were referred early to a SPCC were female (F = 3.638; p < 0.05; N = 226). In addition, patients who were referred early were on average younger than in the group of late referrals (60.33 years vs. 62.65 years). Using univariable logistic regression analyzes (see Table 3), early referral was associated with pulmonary (95% CI, -1.394 to -0.121; p < 0.05), hepatic (95% CI, -1.307 to -0.026; p < 0.05) or other visceral metastasis (95% CI, -1.6 to -0.1; p < 0.05). Psychological distress (95% CI, -3.156 to -0.226; p < 0.05) was another indicator for an early referral. Moreover, late referrals were associated with suffering from ascites (95% CI, 0.126 to 1.839; p < 0.05), with a higher NLR (95% CI, 0.038 to 0.173; p < 0.01) and a higher ECOG performance status (95% CI, 0.409 to 1.2; p < 0.001).

4. Discussion

Although a clear recommendation of early integration of palliative care has already been described, the optimal time point of referral remains unclear (27). Therefore, we conducted a retrospective analyze to identify factors associated with an “early”, “intermediate” and “late” referral to a SPCC. Our study showed that still most of advanced cancer patients were referred late (< 3 months before death) in their course of disease. This is in line with the study of Wentlandt et al., who described referral practices of Canadian oncologists to specialized palliative care and defined characteristics associated with these referrals. Hereby they showed that 83.3% of advanced cancer patients were referred less than 6 months before death (28). Likewise the study of Scibetta et al. (29) showed that from 297 palliative patients 204 (68%) were referred less than 90 days prior to death (late referral). A current study from 2020 from Hausner et al. (8) compared timing of referral before and after the publication of ASCO recommendation supporting early palliative care referral (30). They showed that late referrals (less than 6 months to death) decreased from 68.8–44.8%. However, late referrals were still the majority in both groups. Therefore, further attempts should be made to reach out an early referral that might benefit our patients and their families.

Our analyze clearly showed that pain, social care planning problems and psychological distress were indicators for referring to a SPCC among outpatients with advanced cancer. This data show again the importance of a proper assessment of palliative care needs, where physical symptoms might not be the main burden of our patients and their families. This is in line with a systematic review showing that psychological distress is a common recurrent referral criteria for outpatient palliative cancer care (31). Additionally, a low ECOG Performance Status is an indicator for early referral likewise to the study from Carrasco-Zafra et al. (32). Furthermore, the quantity of assistance with activities of daily living changed significantly from early to late referral. Both indicators show once more the impact of lost of autonomy in our patients.

Moreover, we detected a significant higher intensity of symptoms like “pain”, “weakness”, “tiredness”, “loss of appetite” in patients who were referred late to specialised palliative care. Social problems like “restriction of daily life“, „overburdening of family” and a higher HOPE global sum score were also frequently associated with late referrals. In a previous study from our CCC, we examined needs and requests of cancer patients in the oncology outpatient clinic for palliative care using a patient reported outcome measurement with MIDOS 2 (20). Symptoms like “depression”, “anxiety” and “weakness” were indicators for outpatient’s wish for referral to a SPCC (18). In our study, symptoms like depression or anxiety did not result in an early referral similar to the study of Whadhwa et al. (21). These results might show the difference between the wish of patient and the reasons for a referrer to actually refer a patient to a specialized palliative care unit. Second, a palliative care nurse rated the questionnaire at first referral to the SPCC. Therefore, further analyzes comparing results between self-reported and external assessments would contribute to a better understanding and improvement of patient-centred outcomes. The difference in symptom intensity by early and late referrals are in line with Cheung et al. (33) and Whadwa et al. (21). Cheung et al. analyzed 1366 outpatients with advanced cancer. In their study, gastrointestinal, lung and breast cancer were the most common primary cancer sites of patients referred to a palliative care cancer center. The most distressful symptoms were “poor general wellbeing”, “decreased appetite” and “fatigue”, similar to our study. In addition, Whadwa et al. (21) used the Edmonton Symptom Assessment System (ESAS) to compare early (> 12 months before death) with late referrals (< 6 months before death). Patients who were referred late showed a significant worse overall symptom score as well as the symptoms “tiredness”, “nausea”, “drowsiness”, “loss of appetite” and “overall wellbeing”, similar to most of our results. Therefore, an increasing intensity of these symptoms could be an indicator for a timely referral to specialised palliative care.

Furthermore, our study showed that early referrals were associated with the female gender. This is in line with a previous study from the authors Kwon et al. (34). They compared early referrals (expected survival greater than two years) with late referrals and showed that for example younger patients, female gender and head and neck cancer are indicators for an early referral. Also, a recently study showed that younger age and gynaecologic cancer were more likely to receive a PC referral (31). The Robert Koch Institute (RKI) documented, that women attend cancer screenings more regularly than men (35). This might be one reason for the association between the female gender and earlier referral to palliative care. In addition, it was shown that female gender is more frequently associated with suffering from depression and fear. This could be an explanation for the mentioned psychological distress and younger age as indicator for a timely referral.

The presence of ascites in cancer patients is an indicator for a late referral. Many studies documented that malignant ascites correlates with a poor overall prognosis and a deteriorating in quality of life (36, 37). For example, a retrospective review of 76 patients with malignant ascites by Mackey et al. (37) from 1996, showed that the median survival was 11 weeks from time of diagnosis. Additionally they showed that the presence of low serum albumin and hepatic metastases were significant indicators of poor prognosis.

Some laboratory parameters like NLR, LDH and CRP have been described as indicators of poor prognosis in oncologic patients (38, 39). The NLR is described as a factor related to systemic inflammation, which is associated with cancer growth. Current studies from 2020 and 2021 have suggested that a high baseline NLR is an indicator of lower rates of progression-free and overall survival in various tumour entities like breast, lung and gastrointestinal cancers (40–42). In our study we show that leukocytes, neutrophils, NLR, LDH and CRP are significantly higher in cancer patients who were referred late to a SPCC. The recommendation of these laboratory parameters, some of them well known as prognostic factors, might be further explored in the oncologic palliative care setting as a measure for identifying appropriate candidates for a specialist palliative care referral. There are currently many examples of tools that include both laboratory and clinical or other parameters to assess prognosis (43, 44).

In sum, our data convincingly show that patients with late referrals could have received PC earlier. We propose that not only symptom monitoring, but also other physical (for example the presence of ascites) and laboratory parameters associated with a poor prognosis (like NLR, low serum albumin) might provide useful information for a timely palliative care consultation and therefore its use in the palliative care screening process might be further explored.

5. Limitations

Our study has several limitations. First, the retrospective approach of this study may allow us to miss confounders and generates a sampling bias. Additionally, an adjustment for confounders likewise to the national retrospective cohort study from Allsop et al. (45) is not established, this could leads to different results. Secondly, the results of our monocentric study may not be generalizable. Third, our sample included cancer patients. Factors of patient with non-oncological diseases associated with early and late referral might be further explored in additional studies. Fourth, the implications of these indicators in the clinical practice and future research must be analyzed and discussed in additional studies. Fifth, the characteristics of the referrer were not collected, this might influence early or late referrals given that clinicians who has some palliative care skills or training are more aware of the benefits of palliative care for their patients and families. Sixth, the terms “early” and “late referral” differ between publications, therefore a carefully comparison should be made while comparing results from other publications.

6. Conclusion

Most patients in an outpatient setting are referred late in their course of disease. We showed that female gender, having visceral metastasis and psychological distress are mainly reasons and indicators of an early referral. As a new aspect, laboratory parameters and well known prognostic factors like CRP or NLR could be integrated in existing screening tools for oncologist involved in the decision-making about when to refer to a specialized palliative care unit. Further research is required on combining symptoms and laboratory parameters with timely referral to improve the quality of life in advanced cancer.

7. Declarations

7.1 Ethics approval and consent to participate

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and local ethical review committee of the University of Essen and approved the data analyze (16-6800-BO) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

7.2 Consent for publication

Not applicable.

7.3 Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

7.4 Competing interests

The authors declare that they have no competing interests.

7.5 Funding

Not applicable.

7.6 Authors' contributions

SM collected, analyzed and interpreted the patient data regarding to find indicators for early and late referral. MTew and MCS interpreted and reviewed previous versions of the paper. MTew was a major contributor in writing the manuscript. MF helps by visualisation of results and find the right statistical mean. MS enabled the general conditions. JH helps by acquisition of data. MTeu proofed developed design of survey. All authors read and approved the final manuscript.

7.7 Acknowledgements

Not applicable.

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