End-of-Life Trajectories of Patients With Hematological Malignancies and Patients With Advanced Solid Tumors Visiting the Emergency Department: The Need for a Proactive Integrated Care Approach.

Introduction

The disease trajectories of patients with a hematological malignancy (HM) are diverse, from diseases with an acute manifestation and poor survival to those with a chronic nature. Treatments for HMs, even in patients with a poor clinical condition, are often intensive and are associated with a high risk of severe toxicity (such as graft-versus-host disease), infection, and even death. 1 Because disease trajectories of patients with HM are unpredictable and life threatening, recognition of those who could benefit from a palliative care approach is complicated. 2 - 6 As a consequence, patients with HM are seldom referred to palliative care consultation teams (PCCTs) or hospices, and if they are referred, they often die within days or weeks. 2 , 7 , 8 It is known that palliative care needs of patients with HM are often unmet. 9 According to the definition of the World Health Organization, the aim of a palliative care approach is to improve quality of life of both patients and family; in addition, it can concur with curative systemic treatment along the disease trajectory. 10 This approach includes conversations about the end of life, supportive care, symptom management, and psychosocial support. 9 Insight into the end-of-life trajectory of patients with HM may help identifying cues for initiation of a palliative care approach.

With the occurrence of disease progression or metastases, the palliative phase in patients with a solid tumor (ST) is easier to identify. 6 , 7 , 11 According to Murray, their physical decline is stable and predictable until a steep and short period of decline before death. During the stable phase, health-care providers can proactively assess and support palliative care needs at the end of life. 12 A palliative care approach has been shown to be effective in a various populations of patients with ST in improving quality of life, symptom burden, and even survival. 13 - 15 In patients with HM, palliative care can improve the quality of life after hematopoietic stem cell transplantation already after 2 weeks, as a randomized controlled study by El-Jawahri et al. showed. 16 However, literature indicates that patients with HM need a different proactive approach for early palliative care than the disease trajectory of patients with advanced ST. Conceptual models of integrated palliative care for patients with HM depict palliative care as concurrent with curative care to aim for both cure and care. 17 - 19 So-called trigger events can help identifying patients with HM with palliative care needs to arrange appropriate care. 20 An ED visit is shown to be a potential trigger. 21

Many patients with HM are urged to visit the emergency department (ED) with uncontrollable symptoms or a high symptom burden at home. Consecutively, they are often admitted to the hospital or even to an intensive care unit (ICU), where many of them die. 2 , 22 , 23 These situations can diminish the quality of the end of life of patients with HM and their families. 24 To measure the quality of end-of-life care provided to patients with incurable diseases, Earle et al. constructed the following indicators: receiving chemotherapy in the last 14 days of life, starting a new chemotherapy in the last 30 days of life, >1 ED visit in the last month of life; >1 hospitalization in the last month of life; ICU admission in the last month of life; death in an acute care hospital; lack of hospice admission; and admission to hospice <3 days before death. 24 , 25

The primary objective of this study was to provide insight into the end-of-life trajectory of patients with HM visiting the ED during the last 3 months of life and to compare them with patients with ST. Secondary objective was to compare the quality of end-of-life care in patients with HM and ST.

Patients and Methods

Setting

This mortality follow-back study was conducted at Leiden University Medical Center (LUMC) in Leiden, the Netherlands. The LUMC’s ED is open 24 hours a day, 7 days a week. On average, 80 patients visit the ED every day and about 30 000 patients are evaluated every year. Since 2011, LUMC has a PCCT, which is available to all departments of our center for consultation after patients are referred by their health care provider. This study was part of a larger study on end-of-life trajectories of all patients visiting the ED between 2011 and 2013, approved by LUMC’s Committee of Medical Ethics on May 27, 2013. Written consent was not required according to Dutch Law (WGBO, article 458) and European Law (General Data Protection Regulation).

Patients

All adult patients with HM who died within 3 months after their last ED visit were included. They were compared to patients with ST having advanced cancer, which was defined as not having any curative options or receiving anticancer treatment not aimed at curation. Detailed analysis of patients with ST is published elsewhere. 26 The period of 3 months was chosen because in the Netherlands, an estimated life expectancy of <3 months justifies referral to intensive palliative care at home, in nursing homes, and in hospices. Data collection occurred from May 2011 to January 2013.

Data Collection

For transparent and solid data collection, a code book was designed by 2 members of our PCCT, which contained inclusion and exclusion criteria and description and coding of all variables. 27 Characteristics of disease, referral, ED visit, and follow-up from ED arrival until death were extracted from electronic patient records (EPRs) of eligible patients by 4 trained research assistants. One expert of the PCCT checked for interrater agreement. Electronic patient records were searched for any correspondence with general practitioners (GPs) or PCCT consultations during the 3 months before the ED visit and proactive symptom management plans in files or letters up to 6 weeks before the ED visit. Limitations on life-sustaining treatments (LSTs) were orders on no resuscitation, no ventilation and no admission to the ICU. Discussions on LST did not occur routinely and notes about LSTs were collected by the research assistants. Arrival at the hospital within office hours was defined as from Monday to Friday between 8 am and 6 pm . Performance status was scored using the scale. 28 The main symptom was defined as the referring symptom reported by the attending physician and is part of the structure of reporting in the EPR. This symptom was considered “new” if it was not mentioned in the EPR 3 months before the ED visit; it was considered “acute” if the onset of the symptom was <24 hours. The clinical diagnosis was defined as the conclusion reported by the attending physician in the EPR. Date and place of death were obtained from EPRs. Cause of death in patients with HM was discussed between one expert of the PCCT (E.J.M.d.N.) and a hematologist (C.S.O.) until agreement was reached. Cues for proactive care were communication about the patient’s condition between a health-care provider or PCCT of the hospital and the patient’s GP via a letter, telephone, or transfer; proactive care plans (care plan for anticipation of symptoms, care plans informing the GP, care plans written by the PCCT, PCCT referrals); and limitations on LSTs before the current ED visit. Quality of end-of-life care was assessed using indicators for proactive end-of-life care and indicators of Earle et al: intensive anticancer treatment in the previous 3 months before the ED visit (intensive anticancer treatments include chemotherapy, targeted therapy, stem cell transplantation, and surgery), the number of ED visits in the 6 months before the current ED visit, in-hospital death, death in an acute hospital department (the ED or the ICU), and death in a hospice (as a positive measure). 24

Statistics

Characteristics of patients, referrals, ED visits, and follow-up were analyzed using descriptive statistics. To test differences between patients with HM and ST, we performed χ 2 tests for nominal variables, Mann-Whitney U tests for non-normally distributed continuous or ordinal variables, and Fisher-Freeman-Halton tests for variables with 3 or more categories. Kaplan-Meier’s methodology was used to estimate survival from the ED visit, and survival between patients with HM and ST was tested using a log-rank test. Complete case analyses were performed, using SPSS 23.0 software, and a 2-sided P value <.05 was considered statistically significant.

Results

Patient and Disease Characteristics

Seventy-eight patients with HM and 420 patients with ST died within 3 months after their ED visit ( Table 1 ); more men were in the HM group (67.9% vs 54.5% of patients with ST, P = .026); median age was 63 years (range: 22-94 years). Eastern Cooperative Oncology Group performance score did not differ between patients with HM and ST. Acute myeloid leukemia and multiple myeloma were the most common HM types (26% and 17%, respectively); most STs were located in the digestive tract (27.6%) and in the lung (16.0%; Online Appendix 1). Before the ED visit, limitations on LSTs were discussed with 171 patients (34.3%): with 13 (16.7%) patients with HM and 158 (37.6%) patients with ST ( P < .0001). Four (5.1%) patients with HM and 142 patients with ST (33.8%) had documented limitations; “no limitations” were documented in 9 (11.5%) patients with HM and 16 (3.8%) patients with ST ( P < .0001). Up to 3 months before the ED visit, the PCCT was consulted in 27 patients (1 patient with HM and 26 patients with ST, P = .10). Communication via letters, telephone, and transfers between medical specialists and the patient’s GP had occurred in 67 (85.9%) patients with HM and 332 (79.0%) patients with ST ( P = .15). Proactive care plans were documented for 13 (16.7%) patients with HM and 66 (15.7%) patients with ST ( P = .83).

Referral Characteristics

Patients or their family initiated the ED visit in 37.3% ( Table 2 ). Two hundred fifty-eight (51.8%) came outside office hours. Most common main symptoms were dyspnea (22.1%), pain (17.5%) and fever (11.2%). Patients with HM more often presented with fever (23.1% vs 9.0% of the patients with ST, P = .001); patients with ST more often presented with nausea or vomiting (9.3% vs 2.6% of the patients with HM). Patients had a median of 2 symptoms.

Visit and Follow-Up Characteristics

Patients underwent diagnostic imaging in 64.1% and laboratory tests in 84.1% ( Table 3 ). Most patients were diagnosed with infection or fever (24.5%), bronchopulmonary insufficiency (14.3%), or renal insufficiency (11.8%). In patients with HM, treatment for their main symptoms was initiated at the ED more often than in patients with ST (69.2% vs 54.8%, P = .010). After their ED visit, more patients with HM were hospitalized than in patients with ST (91.0% vs 76.0%, P = .001). The ED visit triggered discussions about LSTs in both patients with HM and ST. After the ED visit, LSTs were documented for 41 (52.6%) patients with HM and 307 (73.1%) patients with ST ( P < .0001). Among these patients, 39 (95.1%) patients with HM and 297 (96.7%) patients with ST had limitations on LSTs ( P = .64). Median survival from the ED visit was 17 days (95% confidence interval: 15-19) and was significantly shorter in patients with HM (15 days vs 18 days, P = .028). In-hospital death occurred in 67.9% of the patients with HM versus 29.5% of the patients with ST; patients with HM died at home in 15.4% versus 38.3% of the patients with ST ( P < .0001). In patients with HM, causes of death were disease progression (46.2%), treatment toxicity (39.7%), or both (9.0%).

Quality of End-of-Life Care

Quality of end-of-life care in patients with HM and ST is shown in Table 4 . Intensive anticancer treatment was administered to 375 (72.4%) of all patients up to 6 months before the ED visit, to 75.6% of the patients with HM versus 71.8% of the patients with ST, P = .48. Patients with HM died more often in hospital compared to patients with ST (67.9% vs 29.5%, P < .0001), in an acute hospital setting (29.5% vs 2.7%, P < .0001), and less often in a hospice (2.6% vs 10.5%, P = .011).

Discussion

This study gives insight into the disease trajectory of patients with HM and into the differences compared to the disease trajectory of patients with an ST visiting the ED in the last 3 months of their lives. Limitations on LSTs were often not discussed in patients with HM before their ED visit, and if these were discussed, patients often had no limitations on LSTs. End-of-life care was considerably more aggressive in patients with HM compared to patients with ST. Patients with HM had a worse survival than patients with ST and more often died in-hospital and in the ICU and seldom in a hospice.

Our results implicate that end-of-life care is aggressive in patients with HM: they scored poorly on 5 of the indicators of quality of end-of-life care by Earle. 24 Our findings are in accordance with international literature reporting that patients with HM receive intensive treatments until death. In a study by Hui et al., patients with HM received significantly more chemotherapy (21%) and targeted therapy (17%) than patients with ST (6% and 5%, respectively). 2 Other studies report that patients with HM often received granulocyte-colony stimulating factor, blood transfusions, and antibiotics and underwent diagnostic imaging, blood sampling, endoscopy, and bone marrow examination in the last 7 days of life. 23 , 29 A French study in patients who died of metastatic lung cancer showed that end-of-life care was less aggressive the earlier palliative care needs were reported in their EPRs: patients sooner stopped with anticancer treatment and they underwent less often invasive ventilation. 30 In patients with pancreatic cancer in the last 30 days of life who were referred to a palliative care service, those with an early referral to a palliative care team visited the ED less often and were less often hospitalized. 31 It thus seems that when palliative care is integrated into oncology care, patients with ST are at a lower risk of aggressive end-of-life care. In our study, limitations on LSTs were seldom discussed with patients with HM, and remarkably, if it was discussed, it was often explicitly stated in their EPRs that there were no limitations on LSTs. A recent integrative systematic review provided more insight into the aspects of this “curative mind-set”: hematologists feel uncomfortable with hospice referrals and discussing approaching death with patients and family; disease progression is considered as personal failure; and they are concerned that mentioning palliative care early in the disease trajectory might scare patients and their relatives. 6 A qualitative study by Prod’homme et al. showed that end-of-life discussions are avoided by hematologists as long as cure is possible; these discussions are perceived to damage the doctor–patient relationship, especially when the patient’s prognosis is uncertain. 32 In addition, hematologists interpret palliative care more often as end-of-life care than medical oncologists do and are less used to involve a palliative care specialist than medical oncologists. 33 It is known that if patients with HM are referred to palliative care, it generally occurs very late in their disease trajectory. 3 , 7 , 11 Although a curative care approach toward patients with HM could be appropriate, the way it is currently practiced discourages timely initiation of a palliative care approach and conversations about the end of life. El-Jawahri et al. reported that 27% of the hospital admissions in acute myeoloid leukemia patients could have been avoided. 34 Reasons were: being discharged too soon after the previous admission, visits for problems that would have been manageable at home, and the lack of timely outpatient follow-up appointments. These reasons are starting points for initiating a palliative care approach to avoid possible aggressive and harmful treatments in vulnerable patients.

Our study suggests that in many patients the ED visit marked deterioration and a transition in disease trajectory and often even the start of the dying phase. After the ED visit or following hospital admission, limitations on LSTs were discussed and documented in 73% of the patients with ST and 53% of the patients with HM. Although efforts were made to discuss these LSTs, still 36% of the patients with HM were subsequently transferred to the ICU. This is in line with literature demonstrating that patients with HM are frequently and more often admitted to ICUs than patients with ST (39% and 8%, respectively). 2 Failure to recognize patients in the end-of-life phase makes them at risk of receiving aggressive treatments in the hospital and may even result in death: in our study, 33% of the patients with HM died in the ICU, compared to 4% of the patients with ST ( P < .0001). 2 Sixty-nine percent of our patients with HM died in the hospital and 40% died as a result of treatment toxicity. Howell et al. showed that, compared to patients with ST, patients with HM had a twice higher risk to die in the hospital. 22 Our findings confirm that patients with HM have unpredictable disease trajectories that can suddenly change from curative to dying: most of our patients died shortly after the ED visit with a median survival of only 15 days. Reasons for difficulties to predict survival and to recognize the transition to the end-of-life trajectory are possibly reversible conditions such as infections, increasing availability of systemic therapies that stimulate continuance of active treatment and increase the risk of lethal complications. 1 , 35 Long-lasting physician–patient relationships are also known to hamper accurate recognition of deterioration. 6 The combination of these factors makes it difficult for physicians to recognize approaching death in patients with HM and to timely prepare them for their approaching death.

A Proactive Integrated Care Approach

We advocate, as Zimmermann, Bruera, LeBlanc, El-Jawahri, Chung, and Button do, the use of an integrated care approach with 2 concurrent tracks: a curative approach and palliative care approach ( Figure 1 ). 16 - 19 , 36 , 37 Integrated care should be initiated early in the disease trajectory if the disease is potentially life threatening (which can be at diagnosis). The first track consists of conventional disease treatment aimed at cure. The second track consists of supportive care following the 4-dimensional principles of palliative care: physical, psychological, social, and spiritual. Importantly, the second track also includes discussions about future problems, treatment choices, hospital admissions, LSTs, and place of death. The palliative care approach has shown to benefit symptom control 37 and quality of life, 38 to decrease ED visits, hospital and ICU admissions and in-hospital deaths, 39 , 40 and might even prolong survival. 41 In the integrated care approach, multidisciplinary discussions and communication across specializations within and outside the medical field are crucial to satisfy care needs. The randomized clinical trial by El-Jawahri et al. demonstrated that inpatient palliative care improved the quality of life of patients with HM already within 2 weeks after hematopoietic stem cell transplantation had taken place. 16

Our pragmatic study provides insight into the care for patients with HM visiting the ED in their end-of-life trajectory and compared it with the disease trajectory of patients with ST. The inclusion of only those patients who died within 3 months after the ED visit is inherent to the mortality follow-back design of this study, but it has introduced selection bias. Although data were collected from 2011 to 2013, they are still relevant since new life-prolonging systemic treatments only further emphasize the need for an integrated care approach. Further research should be directed to identifying the specific palliative care needs of patients with HM and their families and developing interventions to address to those.

We would like to thank Leanne Smit, Tobias Wieles, Mathijs Kruizinga, Iris Groeneveld, Lotte van der Stap, and our colleagues at the Center of Expertise Palliative Care of the LUMC.

Conclusions

Patients with HM who visited the ED in the last 3 months of life are more often hospitalized and die in hospital compared to patients with ST. To improve care during the end-of-life trajectory, especially for patients with HM, palliative care should be timely integrated in standard oncological care.

Supplemental Material

Supplemental Material, Appendix_1 - End-of-Life Trajectories of Patients With Hematological Malignancies and Patients With Advanced Solid Tumors Visiting the Emergency Department: The Need for a Proactive Integrated Care Approach

Click here for additional data file.

Supplemental Material, Appendix_1 for End-of-Life Trajectories of Patients With Hematological Malignancies and Patients With Advanced Solid Tumors Visiting the Emergency Department: The Need for a Proactive Integrated Care Approach by Mary-Joanne Verhoef, Ellen J. M. de Nijs, Claudia S. Ootjers, Marta Fiocco, Anne J. Fogteloo, Christian Heringhaus, Corrie A. M. Marijnen, Nanda Horeweg and Yvette M. van der Linden in American Journal of Hospice and Palliative Medicine®

Authors’ Note: As approved by the Medical Ethics Committee of the LUMC and according to Dutch and European law, informed consent from patients was not necessary because of the retrospective design of this study.

Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD: Mary-Joanne Verhoef https://orcid.org/0000-0002-3796-815X

Supplemental Material: Supplemental material for this article is available online.

References

1 McGrath P Holewa H. Special considerations for haematology patients in relation to end-of-life care: Australian findings . Eur J Cancer Care (Engl) . 2007 ; 16 ( 2 ): 164 – 171 . 17371426 10.1111/j.1365-2354.2006.00745.x

2 Hui D Didwaniya N Vidal M , et al. Quality of end-of-life care in patients with hematologic malignancies: a retrospective cohort study . Cancer . 2014 ; 120 ( 10 ): 1572 – 1578 . 24549743 10.1002/cncr.28614 PMC4013204

3 El-Jawahri AR Abel GA Steensma DP , et al. Health care utilization and end-of-life care for older patients with acute myeloid leukemia . Cancer . 2015 ; 121 ( 16 ): 2840 – 2848 . 25926135 10.1002/cncr.29430 PMC4418225

4 Hui D Bansal S Park M , et al. Differences in attitudes and beliefs toward end-of-life care between hematologic and solid tumor oncology specialists . Ann Oncol . 2015 ; 26 ( 7 ): 1440 – 1446 . 26041765 10.1093/annonc/mdv028 PMC4855240

5 Odejide OO Salas Coronado DY Watts CD Wright AA Abel GA End-of-life care for blood cancers: a series of focus groups with hematologic oncologists . J Oncol Pract . 2014 ; 10 ( 6 ): e396 – 403 . 25294393 10.1200/JOP.2014.001537 PMC5706135

6 Moreno-Alonso D Porta-Sales J Monforte-Royo C Trelis-Navarro J Sureda-Balari A De Sevilla-Ribosa AF Palliative care in patients with haematological neoplasms: an integrative systematic review . Palliat Med . 2018 ; 32 ( 1 ): 79 – 105 . 29130387 10.1177/0269216317735246

7 Hui D Kim SH Kwon JH , et al. Access to palliative care among patients treated at a comprehensive cancer center . Oncologist . 2012 ; 17 ( 12 ): 1574 – 1580 . 23220843 10.1634/theoncologist.2012-0192 PMC3528390

8 O’Connor NR Hu R Harris PS Ache K Casarett DJ Hospice admissions for cancer in the final days of life: independent predictors and implications for quality measures . J Clin Oncol . 2014 ; 32 ( 28 ): 3184 – 3189 . 25154824 10.1200/JCO.2014.55.8817 PMC4171361

9 LeBlanc TW El-Jawahri A When and why should patients with hematologic malignancies see a palliative care specialist? Hematology Am Soc Hematol Educ Program . 2015 ; 2015 : 471 – 478 . 26637760 10.1182/asheducation-2015.1.471

10 World Health Organization . WHO Definition of Palliative Care . Cancer . 2018 http://www.who.int/cancer/palliative/definition/en/ . Accessed May 10, 2019 .

11 Howell DA Shellens R Roman E Garry AC Patmore R Howard MR Haematological malignancy: are patients appropriately referred for specialist palliative and hospice care? A systematic review and meta-analysis of published data . Palliat Med . 2011 ; 25 ( 6 ): 630 – 641 . 21228094 10.1177/0269216310391692

12 Murray SA Kendall M Boyd K Sheikh A Illness trajectories and palliative care . BMJ . 2005 ; 330 ( 7498 ): 1007 – 1011 . 15860828 10.1136/bmj.330.7498.1007 PMC557152

13 Temel JS Greer JA Muzikansky A , et al. Early palliative care for patients with metastatic non-small-cell lung cancer . N Engl J Med . 2010 ; 363 ( 8 ): 733 – 742 . 20818875 10.1056/NEJMoa1000678

14 Bakitas M Lyons KD Hegel MT , et al. Effects of a palliative care intervention on clinical outcomes in patients with advanced cancer: the project ENABLE II randomized controlled trial . JAMA . 2009 ; 302 ( 7 ): 741 – 749 . 19690306 10.1001/jama.2009.1198 PMC3657724

15 Vanbutsele G Pardon K Van Belle S , et al. Effect of early and systematic integration of palliative care in patients with advanced cancer: a randomised controlled trial . Lancet Oncol . 2018 ; 19 ( 3 ): 394 – 404 . 29402701 10.1016/S1470-2045(18)30060-3

16 El-Jawahri A LeBlanc T VanDusen H , et al. Effect of inpatient palliative care on quality of life 2 weeks after hematopoietic stem cell transplantation: a randomized clinical trial . JAMA . 2016 ; 316 ( 20 ): 2094 – 2103 . 27893130 10.1001/jama.2016.16786 PMC5421101

17 Button E Bolton M Chan RJ Chambers S Butler J Yates P A palliative care model and conceptual approach suited to clinical malignant haematology . Palliat Med . 2019 ; 33 ( 5 ): 483 – 485 . 30688149 10.1177/0269216318824489

18 Zimmermann C. Palliative care for patients with hematological malignancies: time for a new model . Leuk Res . 2016 ; 48 : 78 – 79 . 27501270 10.1016/j.leukres.2016.07.012

19 Bruera E Hui D Conceptual models for integrating palliative care at cancer centers . J Palliat Med . 2012 ; 15 ( 11 ): 1261 – 1269 . 22925157 10.1089/jpm.2012.0147 PMC3533890

20 Boyd K Murray SA Recognising and managing key transitions in end of life care . BMJ . 2010 ; 341 : c4863 . 20847023 10.1136/bmj.c4863

21 Grudzen CR Stone SC Morrison RS The palliative care model for emergency department patients with advanced illness . J Palliat Med . 2011 ; 14 ( 8 ): 945 – 950 . 21767164 10.1089/jpm.2011.0011 PMC3180760

22 Howell DA Roman E Cox H , et al. Destined to die in hospital? Systematic review and meta-analysis of place of death in haematological malignancy . BMC Palliat Care . 2010 ; 9 : 9 . 20515452 10.1186/1472-684X-9-9 PMC2892433

23 Cheng BH Sham MM Chan KY Li CW Au HY Intensive palliative care for patients with hematological cancer dying in hospice: analysis of the level of medical care in the final week of life . Am J Hosp Palliat Care . 2015 ; 32 ( 2 ): 221 – 225 . 24259405 10.1177/1049909113512412

24 Earle CC Neville BA Landrum MB , et al. Evaluating claims-based indicators of the intensity of end-of-life cancer care . Int J Qual Health Care . 2005 ; 17 ( 6 ): 505 – 509 . 15985505 10.1093/intqhc/mzi061

25 Earle CC Park ER Lai B Weeks JC Ayanian JZ Block S Identifying potential indicators of the quality of end-of-life cancer care from administrative data . J Clin Oncol . 2003 ; 21 ( 6 ): 1133 – 1138 . 12637481 10.1200/JCO.2003.03.059

26 Verhoef MJ de Nijs E Horeweg N , et al. Palliative care needs of advanced cancer patients in the emergency department at the end of life: an observational cohort study . Support Care Can . 2019 ; 28 ( 3 ): 1097 – 1107 . doi:10.1007/s00520-019-04906-x. 10.1007/s00520-019-04906-x PMC6989579 31197539

27 Gilbert EH Lowenstein SR Koziol-McLain J Barta DC Steiner J. Chart reviews in emergency medicine research: where are the methods? Ann Emerg Med . 1996 ; 27 ( 3 ): 305 – 308 . 8599488 10.1016/s0196-0644(96)70264-0

28 Oken MM Creech RH Tormey DC , et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group . Am J Clin Oncol . 1982 ; 5 ( 6 ): 649 – 655 . 7165009

29 Bruck P Pierzchlewska M Kaluzna-Oleksy M , et al. Dying of hematologic patients—treatment characteristics in a German University hospital . Supp Care Can . 2012 ; 20 ( 11 ): 2895 – 2902 . 10.1007/s00520-012-1417-8 22410860

30 Goldwasser F Vinant P Aubry R , et al. Timing of palliative care needs reporting and aggressiveness of care near the end of life in metastatic lung cancer: a national registry-based study . Cancer . 2018 ; 124 ( 14 ): 3044 – 3051 . 29742292 10.1002/cncr.31536

31 Michael N Beale G O’Callaghan C , et al. Timing of palliative care referral and aggressive cancer care toward the end-of-life in pancreatic cancer: a retrospective, single-center observational study . BMC Palliat Care . 2019 ; 18 ( 1 ): 13 . 30691417 10.1186/s12904-019-0399-4 PMC6350289

32 Prod’homme C Jacquemin D Touzet L Aubry R Daneault S Knoops L Barriers to end-of-life discussions among hematologists: a qualitative study . Palliat Med . 2018 ; 32 ( 5 ): 1021 – 1029 . 29756557 10.1177/0269216318759862

33 LeBlanc TW O’Donnell JD Crowley-Matoka M , et al. Perceptions of palliative care among hematologic malignancy specialists: a mixed-methods study . J Oncol Pract . 2015 ; 11 ( 2 ): e230 – e238 . 25784580 10.1200/JOP.2014.001859 PMC4893821

34 El-Jawahri A Keenan T Abel GA , et al. Potentially avoidable hospital admissions in older patients with acute myeloid leukaemia in the USA: a retrospective analysis . Lancet Haematol . 2016 ; 3 ( 6 ): e276 – 283 . 27264037 10.1016/S2352-3026(16)30024-2

35 Manitta VJ Philip JA Cole-Sinclair MF Palliative care and the hemato-oncological patient: can we live together? A review of the literature . J Palliat Med . 2010 ; 13 ( 8 ): 1021 – 1025 . 20712465 10.1089/jpm.2009.0267

36 LeBlanc TW Roeland EJ El-Jawahri A Early palliative care for patients with hematologic malignancies: is it really so difficult to achieve? Curr Hematol Malig Rep . 2017 ; 12 ( 4 ): 300 – 308 . 28639084 10.1007/s11899-017-0392-z

37 Chung HM Lyckholm LJ Smith TJ Palliative care in BMT . Bone Marrow Transplant . 2009 ; 43 ( 4 ): 265 – 273 . 19151797 10.1038/bmt.2008.436

38 Thomas ML Crisp N Campbell K The importance of quality of life for patients living with myelodysplastic syndromes . Clin J Oncol Nurs . 2012 ; 16 ( Suppl ): 47 – 57 . 22641284 10.1188/12.CJON.S1.47-57

39 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 . 2014 ; 120 ( 11 ): 1743 – 1749 . 24967463 10.1002/cncr.28628 PMC4073257

40 Ansell P Howell D Garry A , et al. What determines referral of UK patients with haematological malignancies to palliative care services? An exploratory study using hospital records . Palliat Med . 2007 ; 21 ( 6 ): 487 – 492 . 17846088 10.1177/0269216307082020

41 Bakitas MA Tosteson TD Li Z , et al. Early versus delayed initiation of concurrent palliative oncology care: patient outcomes in the enable III randomized controlled trial . J Clin Oncol . 2015 ; 33 ( 13 ): 1438 – 1445 . 25800768 10.1200/JCO.2014.58.6362 PMC4404422