Abstract
Purpose
Despite that early integration of palliative care is recommended in advanced cancer patients, referrals to outpatient specialised palliative care (SPC) frequently occur late. Well-defined referral criteria are still missing. We analysed indicators associated with early (ER) and late referral (LR) to SPC of an high volume outpatient unit of a comprehensive cancer center.
Methods
Characteristics, laboratory parameters and symptom burden of 281 patients at first SPC referral were analysed. Timing of referral was categorized as early, intermediate and late (> 12, 3–12 and < 3 months before death). Ordinal logistic regression analysis was used to identify 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 analyses, 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.
Similar content being viewed by others
Explore related subjects
Discover the latest articles, news and stories from top researchers in related subjects.Introduction
Advanced cancer patients should be offered palliative care treatment in a timely manner in combination with oncological cancer therapy [1,2,3,4]. Multiple studies have shown that integration of any modality 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 [5,6,7,8,9,10].
Various conceptual frameworks have been proposed including a recent Delphi study from Hui et al. [11] 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 [12,13,14,15,16,17,18]. A large retrospective cohort study with more than 22,500 patients was able to demonstrate that outpatients had high scores in the Edmonton Symptom Assessment System (ESAS) [19, 20] for tiredness, lack of appetite and impaired wellbeing [21]. 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 [22]. Additionally, differences in gender and cancer subtypes were observed regarding specialised palliative care consultations [23]. Furthermore, current studies of different cancer types showed that laboratory data like the neutrophil-to-lymphocyte ratio (NLR) is a predictor for reduced overall survival in cancer patients.
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 [24]. In this context, outpatient care and treatment options such as specialised palliative care are increasingly coming to the forefront [25]. Therefore, many oncological comprehensive cancer centres (CCC) integrate nowadays a specialised palliative care consultation (SPCC) for outpatients into their routine care [26,27,28].
One of these CCC in Germany established a SPCC in a high volume outpatient clinic for cancer patients. A median of 60 patients had at least one SPCC every year [29]. During a routine SPCC in germany, the Hospice and Palliative Care Evaluation (HOPE) Symptoms and Problem Checklist is used as common tool for documentation [30].
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 [31].
Although many referral criteria and clinical indicators have been already described, the role of laboratory parameters as predictors of early referral to SPCC remains unexamined. Therefore, our primary objective was to analyse symptom burden using the previously validated HOPE score, clinical indicators and timing of referral to a SPCC in our patient population. Furthermore we explored the role of NLR as a laboratory indicator for early referral to SPCC.
In second point, we hypothesized that the symptom burden would be lower in early referrals. Based on previous studies where the female gender was more common in groups of early referral we hypothesis the gender could be a predictor for early referral [32]. Even gynaecological cancer types were described as factor to be referred earlier to a SPCC [23].
Methods
Study design
In this retrospective, non-interventional study based on medical records, we reviewed 310 patients who were referred to the outpatient area of SPCC in a German CCC between November 2013 and December 2020. Documentation at first referral to a SPCC and patients’ characteristics in the medical charts were evaluated. All referring physicians had completed the German hematology and oncology medical specialty. The time of death was obtained from the local residents' registration office.
Demographics
Participants in our study had to meet the following inclusion criteria: age above 18 years and a histologically confirmed solid cancer type according to the Union for International Cancer Control (UICC) stage IV at the time of first referral to a SPCC.
In addition to demographic information such as sex, age, cancer diagnosis, date of first diagnosis and date of metastasis, we collected information with the HOPE Symptoms and Problem Checklist such as chemotherapy treatment, location of metastasis, the reason for referral to the SPCC listed by the attending physician, the existence of a level of care and the patient's physical condition.
Timing of referral
We also documented information related to the timing of referral to palliative care in relation to death as follows: first palliative care referrals more than one year before the patient ‘s death were classified as „early “ (ER); referrals between 3 and 12 months before death were classified as „intermediate “; and referrals made less than 3 months before death were classified as „late “ (LR) [32].
HOPE
The German Hospice and Palliative Care Evaluation (HOPE) Symptoms and Problem Checklist is used for standard documentation in German inpatient and outpatient hospice and palliative care services since 1999 [33, 34]. The German Association for Palliative Medicine, the German Association for Cancer and the German Hospice and Palliative Care Association developed and validated this checklist. The HOPE Checklist is utilised by all disciplines involved in the care of patient [31]. This checklist includes 16 different items, eight for physical symptoms (pain, nausea, vomiting, dyspnoea, constipation, weakness, loss of appetite, tiredness), two special nursing problems (wound care, assistance with activities of daily living [ADLs]), four psychological issues (depression, anxiety, confusion, tension), two social topics (organization of care, overburdening of family) and one category for an other problem not previously mentioned. Symptoms are documented in a 4-point-Likert-Scale (0 = none, 1 = mild, 2 = moderate and 3 = strong) by a palliative care nurse [35, 36]. The global sum score for each patient is calculated ranking from minimum 0 to maximum 51 [33]. A low score means no complains, a high score means a high symptom burden.
ECOG
The Performance status scale from the Eastern Cooperative Oncology Group (ECOG) is a simple and validated tool commonly used in patients with cancer to quantify general wellbeing, physical status and estimate survival [37, 38]. The graduation is according to a 0 to 5 scale, where 0 indicates optimal health and 5 indicates death. A palliative care nurse documented the ECOG status at the time of first specialised palliative care consultation.
Laboratory parameters
We abstracted commonly used laboratory parameters, which includes leucocytes [per nL], neutrophil granulocytes [per nL], neutrophil-to-lymphocyte ratio (NLR), haemoglobin [g/dL], total protein [g/dL], albumin [g/dL], CRP [mg/dL] and LDH [U/L], from the routine database of the hospital information system at the time of initial presentation. We defined laboratory parameters as valid if they were documented within a time interval of 4 weeks from the initial presentation.
Statistical analyses
Data management and analysis were conducted using the program Statistical Program for Social Sciences SPSS version 26.0 (IBM, New York). To characterize the patients at first referral and in context of time of referral we used descriptive statistics. We used univariable logistic regression analyses to find indicators of early and late referral. In addition, multivariate analysis was performed to examine the influence of the cancer type on early referral. One-way ANOVA was used for group-differences. To analyse the HOPE symptom burden (as a sum score and each item separately) and laboratory parameters related to the time of referral Kruskal–Wallis-tests were used. The significance level was set at p < 0.05 for all tests.
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 specialised 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 to 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 had 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 analysis 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 multivariate analysis, the cancer type (diagnosis) did not predict an early referral (F (1,7) = 1,332; p = 0.244). Univariable logistic regression analysis (see Table 3) shows that 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. In contrast, 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).
Analyses to timing of referral
Symptom burden differed in subgroups of early, intermediate and late referral as shown in Table 4. Patients who were referred late had higher HOPE global sum scores (16.1 ± 6.4 vs. 13.0 ± 5.4; p < 0.01) as well as worsening pain (1.6 ± 1.0 vs. 1.4 ± 1.1; p < 0.05), weakness (2.1 ± 0.8 vs. 1.4 ± 0.8; p < 0.001), loss of appetite (1.5 ± 1.1 vs. 0.8 ± 0.8; p < 0.001), tiredness (1.9 ± 0.9 vs. 1.4 ± 0.7; p < 0.001), assistance with activities of daily living (1.4 ± 0.98 vs. 0.8 ± 0.7; p < 0.001) and organisation of care (0.9 ± 0.9 vs. 0.5 ± 0.6; p < 0.01). Other symptoms did not differ regarding time of referral. Additionally through 2013 to 2020 there were no difference in symptom burden (early referral) over the years (F (1,7) = 1.445; N = 152; R2 = 0.066; p = 0.192).
Analyses of the laboratory parameters
The laboratory parameters analysed differed significantly when comparing referral groups. As illustrated in Table 5, the leukocytes (9.1 ± 5.4 vs. 6.8 ± 4.7; p < 0.01), the neutrophil granulocytes (7.4 ± 5.2 vs. 4.8 ± 4.1; p < 0.001), the CRP (7.8 ± 7.7 vs. 1.2 ± 1.8; p < 0.001), the NLR (10.1 ± 13.9 vs. 4.9 ± 3.4; p < 0.001) and the LDH (479.9 ± 508.9 vs. 277.7 ± 182.6; p < 0.001) were significant higher in the late referral group. Other objective parameters like haemoglobin (10.3 ± 1.9 vs. 11.8 ± 1.4; p < 0.001), total protein (6.1 ± 0.8 vs. 6.6 ± 0.4; p < 0.01) and albumin (3.5 ± 0.5 vs. 4.2 ± 0.4; p < 0.001) were significantly lower in the group of late referrals.
Discussion
Although a clear recommendation for early integration of palliative care has already been described, the optimal time point of referral remains unclear [39]. Therefore, we conducted a retrospective analysis 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 the course of their disease. This is in line with the study by 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 [40]. Likewise a study by Scibetta et al. [41] showed that from 297 palliative patients 204 (68%) were referred less than 90 days prior to death (late referral). A current study from 2020 by Hausner et al. [13] compared timing of referral before and after the publication of ASCO recommendation supporting early palliative care referral [42]. They showed that late referrals (less than 6 months to death) decreased from 68.8% to 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. In our study, the median time from first time of referral to death of all referrals was 6.38 months, which is better than in other published studies [35, 39]. Since 2013, our oncological CCC has integrated a specialised palliative care consultation (SPCC) for outpatients into their routine care as a measure of quality of care, which might be the reason for this result.
Our analysis 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 again shows the importance of a proper coverage of palliative care needs, where physical symptoms might not be the main burden of our patients and their families. These results are in line with a systematic review showing that psychological distress is a common recurrent referral criteria for outpatient palliative cancer care (62). Additionally, a low ECOG Performance Status is an indicator for early referral likewise to the study by Carrasco-Zafra et al. [43]. Moreover, the quantity of assistance with activities of daily living changed significantly from early to late referral. Both indicators show once more the impact of loss of autonomy in our patients. To our best knowledge, only two other studies reported on cancer patients’ reason for referral to palliative care [32, 44]. However, these studies only made very rough specifications about the reason for referral, divided into only four aspects: palliative planning, end-of-life care and pain control and/or symptom management.
Moreover, we detected a significant higher intensity of symptoms like “pain”, “weakness”, “tiredness”, and “loss of appetite” in late referrals 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 [30]. Symptoms like “depression”, “anxiety” and “weakness” were indicators for outpatient’s wish for referral to a SPCC [31]. In our study, symptoms like depression or anxiety did not result in an early referral similar to the study of Whadhwa et al. [32]. These results might show the difference between the wish of patient and the reasons for a physician to refer a patient to a specialised palliative care consultation hour. Second, a palliative care nurse rated the questionnaire at first referral to the SPCC. Therefore, further analysis comparing results between self-reported and external assessments would contribute to a better understanding and improvement of patient-centred outcomes. Our reported difference in symptom intensity by early and late referrals are in line with Cheung et al. [45] and Whadwa et al. [32]. The first study analysed 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. [32] 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 significantly 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 independently of the special type of cancer. This is in line with a previous study from the authors Kwon et al. [46]. They compared early referrals (expected survival greater than two years) with late referrals and showed that younger age, female gender, alcoholism and head and neck cancer are indicators for an early referral. Also, a recently study showed that younger age and gynaecological cancer were more likely to receive a PC referral (63). One reason for the association between the female gender and earlier referral to palliative care may be that women attend cancer screenings more regularly than men, as stated by the German health insurance provider “BARMER GEK” [47]. Furthermore, the Robert Koch Institute (RKI), one of the leading biomedical research institutions of the German government, presented similar results years before [48]. Additionally, a further study showed that female gender is more frequently associated with suffering from depression and fear [49,50,51], so this could be an explanation for the previously mentioned correlation between psychological distress and younger age as indicator for a timely referral.
In contrast, 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 deterioration in quality of life [52,53,54]. For example, a retrospective review of 76 patients with malignant ascites by Mackey et al. [55] 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 [56,57,58,59,60]. 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 NLR is an indicator of lower rates of progression-free and overall survival in various tumour entities such as breast, lung, gastrointestinal and head-and neck cancers [61,62,63,64,65]. For example, Chen et al. [61] analysed changes in NLR among 101 advanced non-small cell lung cancer (NSCLC) patients undergoing therapy with programmed cell death 1 inhibitors. They showed that a high baseline NLR (defined as greater than 4.5) and increased post-treatment NLR were associated with significant increased risk of death and disease progression. 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. Especially previous studies could proved laboratory data included in prognostic scales are potentially helpful in clinical practice [66]. However, until now they are not integrated in PC routine screening tools, which are frequently used [11, 67, 68]. Furthermore our results show a tendency to use laboratory values as early indicators for first SPCC and not only for the last thirty days before death as currently proven by Stone et al. [69]. Therefore, part of these laboratory parameters should be integrated in palliative care screening tools as measure for identifying appropriate candidates for a specialist palliative care referral.
In sum, our data convincingly supports that patients with late referrals could have received PC earlier, potentially leading to a better outcome. We propose that not only symptom monitoring, but other physical (for example the presence of ascites) and especially laboratory parameters associated with a poor prognosis (such as NLR and low serum albumin) as well, might provide useful information for a timely specialised palliative care consultation. Therefore, its use in the palliative care screening process should be further explored and integrated in actual discussion of one universal screening instrument.
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 by Allsop et al. [70] is not established, this could leads to different results. Secondly, the results of our monocentric study may not be generalizable. Third, our sample included only patients with oncological diseases; the extent to witch these factors are applicable to patients with non-oncological diseases might be further explored in additional studies. Fourth, the implications of these indicators in the clinical practice and future research should be analysed 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 have 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 careful comparison should be made while comparing results from other publications.
Conclusion
Most patients in an outpatient setting are referred late in the course of their 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.
Availability of data and materials
Data is available from the corresponding author on reasonable request.
References
Kaasa S, Loge JH, Aapro M, Albreht T, Anderson R, Bruera E, Brunelli C, Caraceni A, Cervantes A, Currow DC, Deliens L, Fallon M, Gomez-Batiste X, Grotmol KS, Hannon B, Haugen DF, Higginson IJ, Hjermstad MJ, Hui D, Jordan K, Kurita GP, Larkin PJ, Miccinesi G, Nauck F, Pribakovic R, Rodin G, Sjogren P, Stone P, Zimmermann C, Lundeby T. Integration of oncology and palliative care: a Lancet Oncology Commission. Lancet Oncol. 2018;19:e588–653.
Bakitas M, Lyons KD, Hegel MT, Balan S, Barnett KN, Brokaw FC, Byock IR, Hull JG, Li Z, McKinstry E, Seville JL, Ahles TA. The project ENABLE II randomized controlled trial to improve palliative care for rural patients with advanced cancer: baseline findings, methodological challenges, and solutions. Palliat Support Care. 2009;7:75–86.
Ferrell BR, Temel JS, Temin S, Smith TJ. Integration of Palliative Care Into Standard Oncology Care: ASCO Clinical Practice Guideline Update Summary. J Oncol Pract. 2017;13:119–21.
Hui D, Kim YJ, Park JC, Zhang Y, Strasser F, Cherny N, Kaasa S, Davis MP, Bruera E. Integration of oncology and palliative care: a systematic review. Oncologist. 2015;20:77–83.
Temel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S, Jackson VA, Dahlin CM, Blinderman CD, Jacobsen J, Pirl WF, Billings JA, Lynch TJ. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363:733–42.
Irwin KE, Greer JA, Khatib J, Temel JS, Pirl WF. Early palliative care and metastatic non-small cell lung cancer: potential mechanisms of prolonged survival. Chron Respir Dis. 2013;10:35–47.
Greer JA, Jackson VA, Meier DE, Temel JS. Early integration of palliative care services with standard oncology care for patients with advanced cancer. CA Cancer J Clin. 2013;63:349–63.
Vanbutsele G, Pardon K, Van Belle S, Surmont V, De Laat M, Colman R, Eecloo K, Cocquyt V, Geboes K, Deliens L. Effect of early and systematic integration of palliative care in patients with advanced cancer: a randomised controlled trial. Lancet Oncol. 2018;19:394–404.
Aktas A, Rybicki LA, Walsh D. The impact of symptom clusters on survival in patients with advanced cancer. J Clin Oncol. 2010;28:9145–9145.
Wright AA, Keating NL, Balboni TA, Matulonis UA, Block SD, Prigerson HG. Place of death: correlations with quality of life of patients with cancer and predictors of bereaved caregivers’ mental health. J Clin Oncol. 2010;28:4457–64.
Hui D, Mori M, Watanabe SM, Caraceni A, Strasser F, Saarto T, Cherny N, Glare P, Kaasa S, Bruera E. Referral criteria for outpatient specialty palliative cancer care: an international consensus. Lancet Oncol. 2016;17:e552–9.
Hui D, Anderson L, Tang M, Park M, Liu D, Bruera E. Examination of referral criteria for outpatient palliative care among patients with advanced cancer. Support Care Cancer. 2020;28:295–301.
Hausner D, Tricou C, Mathews J, Wadhwa D, Pope A, Swami N, Hannon B, Rodin G, Krzyzanowska MK, Le LW, Zimmermann C. Timing of Palliative Care Referral Before and After Evidence from Trials Supporting Early Palliative Care. Oncologist. 2021;26(4):332-40. https://doi.org/10.1002/onco.13625.
Gemmell R, Yousaf N, Droney J. “Triggers” for early palliative care referral in patients with cancer: a review of urgent unplanned admissions and outcomes. Support Care Cancer. 2020;28:3441–9.
Hui D, Kim SH, Roquemore J, Dev R, Chisholm G, Bruera E. Impact of timing and setting of palliative care referral on quality of end-of-life care in cancer patients. Cancer-Am Cancer Soc. 2014;120:1743–9.
Ahluwalia SC, Fried TR. Physician factors associated with outpatient palliative care referral. Palliat Med. 2009;23:608–15.
Caraceni A, Lo Dico S, Zecca E, Brunelli C, Bracchi P, Mariani L, Garassino MC, Vitali M. Outpatient palliative care and thoracic medical oncology: Referral criteria and clinical care pathways. Lung Cancer. 2020;139:13–7.
Iqbal J, Sutradhar R, Zhao H, Howell D, O’Brien MA, Seow H, Dudgeon D, Atzema C, Earle CC, DeAngelis C, Sussman J, Barbera L. Operationalizing Outpatient Palliative Care Referral Criteria in Lung Cancer Patients: A Population-Based Cohort Study Using Health Administrative Data. J Palliat Med. 2020;23:670–7.
Hui D, Bruera E. The Edmonton Symptom Assessment System 25 Years Later: Past Present, and Future Developments. J Pain Symptom Manage. 2017;53:630–43.
Bruera E, Kuehn N, Miller MJ, Selmser P, Macmillan K. The Edmonton Symptom Assessment System (ESAS): a simple method for the assessment of palliative care patients. J Palliat Care. 1991;7:6–9.
Bubis LD, Davis LE, Coburn NG, Mahar AL. Authors’ Reply to the Response to "Patient-Reported Symptom Severity Among 22,650 Cancer Outpatients in the Last 6 Months of Life’’. J Pain Symptom Manag. 2020;59:E3–4.
Cheung WY, Barmala N, Zarinehbaf S, Rodin G, Le LW, Zimmermann C. The association of physical and psychological symptom burden with time to death among palliative cancer outpatients. J Pain Symptom Manage. 2009;37:297–304.
de Oliveira Valentino TC, Paiva BSR, de Oliveira MA, Hui D, Paiva CE. Factors associated with palliative care referral among patients with advanced cancers: a retrospective analysis of a large Brazilian cohort. Support Care Cancer. 2018;26:1933–41.
Hoerger M, Greer JA, Jackson VA, Park ER, Pirl WF, El-Jawahri A, Gallagher ER, Hagan T, Jacobsen J, Perry LM, Temel JS. Defining the Elements of Early Palliative Care That Are Associated With Patient-Reported Outcomes and the Delivery of End-of-Life Care. J Clin Oncol. 2018;36:1096–102.
Barton MK. Early outpatient referral to palliative care services improves end-of-life care. CA Cancer J Clin. 2014;64:223–4.
Berendt J, Stiel S, Simon ST, Schmitz A, van Oorschot B, Stachura P, Ostgathe C. Integrating Palliative Care Into Comprehensive Cancer Centers: Consensus-Based Development of Best Practice Recommendations. Oncologist. 2016;21:1241–9.
Muir JC, Daly F, Davis MS, Weinberg R, Heintz JS, Paivanas TA, Beveridge R. Integrating palliative care into the outpatient, private practice oncology setting. J Pain Symptom Manage. 2010;40:126–35.
Zimmermann C, Riechelmann R, Krzyzanowska M, Rodin G, Tannock I. Effectiveness of specialized palliative care: a systematic review. JAMA. 2008;299:1698–709.
Berendt J, Thomas M, Neukirchen M, Schwartz J, Hense J, Tewes M. Integration of Palliative Care into the Comprehensive Cancer Center of Germany - Consultation Hours and Fellowship Rotations of the Specialized Palliative Care. Dtsch Med Wochenschr. 2018;143:e139–45.
Stiel S, M.E.B., Matthes L, Ostgathe C, Elsner F, Radbruch L. Validerung der neuen Fassung des Minimalen Dokumentationssystems (/MIDOS2) für Patienten in der Palliativmedizin. Der Schmerz. 2010;24:596–604.
Tewes M, Rettler T, Wolf N, Hense J, Schuler M, Teufel M, Beckmann M. Predictors of outpatients’ request for palliative care service at a medical oncology clinic of a German comprehensive cancer center. Support Care Cancer. 2018;26:3641–7.
Wadhwa D, Popovic G, Pope A, Swami N, Le LW, Zimmermann C. Factors Associated with Early Referral to Palliative Care in Outpatients with Advanced Cancer. J Palliat Med. 2018;21:1322–8.
Stiel S, Pollok A, Elsner F, Lindena G, Ostgathe C, Nauck F, Radbruch L. Validation of the Symptom and Problem Checklist of the German Hospice and Palliative Care Evaluation (HOPE). J Pain Symptom Manage. 2012;43:593–605.
Lindena G, Nauck F, Bausewein C, Neuwohner K, Heine O, Schulenberg D, Radbruch L, Kerndokumentation Arbeitsgruppe, furPalliativeinrichtungen in D. Quality assurance in palliative medicine–results of the core documentation of 1999–2002. Z Arztl Fortbild Qualitatssich. 2005;99:555–65.
Lee G, Kim HS, Lee SW, Park YR, Kim EH, Lee B, Hu YJ, Kim KA, Kim D, Cho HY, Kang B, Choi HJ. Pre-screening of patient-reported symptoms using the Edmonton Symptom Assessment System in outpatient palliative cancer care. Eur J Cancer Care (Engl). 2020;29:e13305.
Lindena G, Wellmann A, Ostgathe C, Radbruch L, Nauck F, Hope K. Ambulante Palliativversorgung in Deutschland – in HOPE dokumentierte. Erfahrungen Z Palliativmed. 2011;12:27–32.
Conill C, Verger E, Salamero M. Performance status assessment in cancer patients. Cancer-Am Cancer Soc. 1990;65:1864–6.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649–55.
Jordan RI, Allsop MJ, ElMokhallalati Y, Jackson CE, Edwards HL, Chapman EJ, Deliens L, Bennett MI. Duration of palliative care before death in international routine practice: a systematic review and meta-analysis. BMC Med. 2020;18:368.
Wentlandt K, Krzyzanowska MK, Swami N, Rodin GM, Le LW, Zimmermann C. Referral practices of oncologists to specialized palliative care. J Clin Oncol. 2012;30:4380–6.
Scibetta C, Kerr K, McGuire J, Rabow MW. The Costs of Waiting: Implications of the Timing of Palliative Care Consultation among a Cohort of Decedents at a Comprehensive Cancer Center. J Palliat Med. 2016;19:69–75.
Schnipper LE, Smith TJ, Raghavan D, Blayney DW, Ganz PA, Mulvey TM, Wollins DS. American Society of Clinical Oncology identifies five key opportunities to improve care and reduce costs: the top five list for oncology. J Clin Oncol. 2012;30:1715–24.
Carrasco-Zafra MI, Gómez-García R, Ocaña-Riola R, Martín-Roselló ML, Blanco-Reina E. Level of Palliative Care Complexity in Advanced Cancer Patients: A Multinomial Logistic Analysis. J Clin Med. 2020;9(6):1960. https://doi.org/10.3390/jcm9061960.
Riechelmann RP, Krzyzanowska MK, O’Carroll A, Zimmermann C. Symptom and medication profiles among cancer patients attending a palliative care clinic. Support Care Cancer. 2007;15:1407–12.
Cheung WY, Le LW, Zimmermann C. Symptom clusters in patients with advanced cancers. Support Care Cancer. 2009;17:1223–30.
Kwon JH, Hui D, Chisholm G, Ha C, Yennurajalingam S, Kang JH, Bruera E. Clinical characteristics of cancer patients referred early to supportive and palliative care. J Palliat Med. 2013;16:148–55.
BARMER-Auswertung – Männer bleiben Vorsorgemuffel, published on 30.03.2021, https://www.barmer.de/presse/presseinformationen/2021-presse-archiv/krebsfrueherkennung-299968. In: Editor (ed)^(eds) Book BARMER-Auswertung – Männer bleiben Vorsorgemuffel, published on 30.03.2021, https://www.barmer.de/presse/presseinformationen/2021-presse-archiv/krebsfrueherkennung-299968. BARMER-Arztreport 2021, City.
Robert-Koch-Institut (Berlin) (Hrsg) 2012 Daten und Fakten: Ergebnisse der Studie »Gesundheit in Deutschland aktuell 2010«. Beiträge zur Gesundheitsberichterstattung des Bundes. RKI
Walsh D, Donnelly S, Rybicki L. The symptoms of advanced cancer: relationship to age, gender, and performance status in 1,000 patients. Support Care Cancer. 2000;8:175–9.
Lidstone V, Butters E, Seed PT, Sinnott C, Beynon T, Richards M. Symptoms and concerns amongst cancer outpatients: identifying the need for specialist palliative care. Palliat Med. 2003;17:588–95.
Donnelly S, Walsh D, Rybicki L. The symptoms of advanced cancer: identification of clinical and research priorities by assessment of prevalence and severity. J Palliat Care. 1995;11:27–32.
Parsons SL, Watson SA, Steele RJ. Malignant ascites Br J Surg. 1996;83:6–14.
Runyon BA. Care of patients with ascites. N Engl J Med. 1994;330:337–42.
Ayantunde AA, Parsons SL. Pattern and prognostic factors in patients with malignant ascites: a retrospective study. Ann Oncol. 2007;18:945–9.
Mackey JR, Venner PM. Malignant ascites: demographics, therapeutic efficacy and predictors of survival. Can J Oncol. 1996;6:474–80.
Koukourakis MI, Giatromanolaki A, Sivridis E, Bougioukas G, Didilis V, Gatter KC, Harris AL, Tumour, Angiogenesis Research G. Lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis. Br J Cancer. 2003;89:877–85.
Suh SY, Ahn HY. Lactate dehydrogenase as a prognostic factor for survival time of terminally ill cancer patients: a preliminary study. Eur J Cancer. 2007;43:1051–9.
Jurisic V, Radenkovic S, Konjevic G. The Actual Role of LDH as Tumor Marker, Biochemical and Clinical Aspects. Adv Exp Med Biol. 2015;867:115–24.
Amano K, Maeda I, Morita T, Miura T, Inoue S, Ikenaga M, Matsumoto Y, Baba M, Sekine R, Yamaguchi T, Hirohashi T, Tajima T, Tatara R, Watanabe H, Otani H, Takigawa C, Matsuda Y, Nagaoka H, Mori M, Kinoshita H. Clinical Implications of C-Reactive Protein as a Prognostic Marker in Advanced Cancer Patients in Palliative Care Settings. J Pain Symptom Manage. 2016;51:860–7.
Allin KH, Nordestgaard BG. Elevated C-reactive protein in the diagnosis, prognosis, and cause of cancer. Crit Rev Clin Lab Sci. 2011;48:155–70.
Chen S, Li R, Zhang Z, Huang Z, Cui P, Jia W, Zhang S, Tao H, Wang L, Li X, Wang J, Ma J, Liu Z, Huang D, Zheng X, Saito Y, Ichiki Y, Hu Y. Prognostic value of baseline and change in neutrophil-to-lymphocyte ratio for survival in advanced non-small cell lung cancer patients with poor performance status receiving PD-1 inhibitors. Transl Lung Cancer Res. 2021;10:1397–407.
Glare PA, Chow K. Validation of a Simple Screening Tool for Identifying Unmet Palliative Care Needs in Patients With Cancer. J Oncol Pract. 2015;11:e81-86.
Nemoto T, Endo S, Isohata N, Takayanagi D, Nemoto D, Aizawa M, Utano K, Togashi K. Change in the neutrophil-to-lymphocyte ratio during chemotherapy may predict prognosis in patients with advanced or metastatic colorectal cancer Mol. Clin Oncol. 2021;14:107.
Patil R, Pandit P, Palwe V, Patil R, Gandhe S, Kate S, Yasam VR, Nagarkar R. The predictive role of neutrophil-to-lymphocyte ratio in the outcomes of patients with sarcomatoid carcinoma of oral cavity. Eur Arch Otorhinolaryngol. 2022;279(1):433-41. https://doi.org/10.1007/s00405-021-06800-x.
Duan J, Pan L, Yang M. Preoperative elevated neutrophil-to-lymphocyte ratio (NLR) and derived NLR are associated with poor prognosis in patients with breast cancer: A meta-analysis Medicine (Baltimore). 2018;97: e13340
Lee SH, Lee JG, Choi YJ, Seol YM, Kim H, Kim YJ, Yi YH, Tak YJ, Kim GL, Ra YJ, Lee SY, Cho YH, Park EJ, Lee Y, Choi J, Lee SR, Kwon RJ, Son SM. Prognosis palliative care study, palliative prognostic index, palliative prognostic score and objective prognostic score in advanced cancer: a prospective comparison. BMJ Support Palliat Care. 2021.
Ostgathe C, Wendt KN, Heckel M, Kurkowski S, Klein C, Krause SW, Fuchs FS, Bayer CM, Stiel S. Identifying the need for specialized palliative care in adult cancer patients - development and validation of a screening procedure based on proxy assessment by physicians and filter questions. BMC Cancer. 2019;19:646.
van Wijmen MPS, Schweitzer BPM, Pasman HR, Onwuteaka-Philipsen BD. Identifying patients who could benefit from palliative care by making use of the general practice information system: the Surprise Question versus the SPICT. Fam Pract. 2020;37:641–7.
Stone P, White N, Oostendorp LJM, Llewellyn H, Vickerstaff V. Comparing the performance of the palliative prognostic (PaP) score with clinical predictions of survival: A systematic review. Eur J Cancer. 2021;158:27–35.
Allsop MJ, Ziegler LE, Mulvey MR, Russell S, Taylor R, Bennett MI. Duration and determinants of hospice-based specialist palliative care: A national retrospective cohort study. Palliat Med. 2018;32:1322–33.
Acknowledgements
Not applicable.
Funding
Open Access funding enabled and organized by Projekt DEAL. The authors did not receive support from any organization for the submitted manuscript.
Author information
Authors and Affiliations
Contributions
MS, MTeu and MTew conceived of the presented idea and gave the general conditions. SM developed the hypothesis and performed the computations. MF verified the analytical methods. SM wrote the manuscript in consultation with MSal, JH and MTew. All authors discussed the results and contributed to the final manuscript. The author(s) read and approved the final manuscript.
Corresponding author
Ethics declarations
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 analysis (16–6800-BO) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
Müller, S., Fink, M., Hense, J. et al. Palliative care outpatients in a German comprehensive cancer center—identifying indicators for early and late referral. BMC Palliat Care 21, 221 (2022). https://doi.org/10.1186/s12904-022-01114-z
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/s12904-022-01114-z