Palliative care referral criteria and outcomes in cancer and heart failure: a systematic review of literature

Background Cardiotoxicity resulting in heart failure (HF) is among the most dreaded complications of cancer therapy and can significantly impact morbidity and mortality. Leading professional societies in cardiology and oncology recommend improved access to hospice and palliative care (PC) for patients with cancer and advanced HF. However, there is a paucity of published literature on the use of PC in cardio-oncology, particularly in patients with HF and a concurrent diagnosis of cancer. Aims To identify existing criteria for referral to and early integration of PC in the management of cases of patients with cancer and patients with HF, and to identify assessments of outcomes of PC intervention that overlap between patients with cancer and patients with HF. Design Systematic literature review on PC in patients with HF and in patients with cancer. Data sources Databases including Ovid Medline, Ovid Embase, Cochrane Library, and Web of Science from January 2009 to September 2020. Results Sixteen studies of PC in cancer and 14 studies of PC in HF were identified after screening of the 8647 retrieved citations. Cancer and HF share similarities in their patient-reported symptoms, quality of life, symptom burden, social support needs, readmission rates, and mortality. Conclusion The literature supports the integration of PC into oncology and cardiology practices, which has shown significant benefit to patients, caregivers, and the healthcare system alike. Incorporating PC in cardio-oncology, particularly in the management of HF in patients with cancer, as early as at diagnosis, will enable patients, family members, and healthcare professionals to make informed decisions about various treatments and end-of-life care and provide an opportunity for patients to participate in the decisions about how they will spend their final days.


Introduction
Cancer and heart disease are the leading causes of death in the United States [1]. The intersection of both is addressed by a new multidisciplinary specialty known as cardio-oncology, which focuses on cardiovascular care in patients with cancer. Among the most dreaded complications of cancer therapy is heart failure (HF), which can occur acutely during the therapy or arise several years after completion of the therapy. The burden of disease and its associated impact on the patient and caregiver in cancer and HF are exceedingly high and compounded when both diseases coexist. An interdisciplinary palliative care (PC) intervention can improve the patient's quality of life, while minimizing caregiver distress and aggressive measures at the end of life. The World Health Organization (WHO) defines PC as "an approach that improves the quality of life of patients and their families, facing the problem associated with life threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual." The WHO recommends that PC should be available to everyone suffering from lifethreatening diseases and should be started early in the illness trajectory [2].
In oncology patients, one of the key barriers to early PC referral is the misunderstanding that PC is only provided at the end of life once patients have exhausted all cancer treatment options. Oftentimes, PC is misinterpreted for hospice or end of life care. Therefore, it is crucial to differentiate between PC and hospice care. Hospice is comfort care without curative intent and is used when the patient no longer has curative options or attempts to cure the person's illness are stopped and the individual is approaching the end of life [3]. Whereas in PC, patients may receive medical care for their symptoms, along with treatment intended to cure their serious illness. PC is meant to enhance a person's current care by focusing on quality of life for them and their family.
The traditional model of PC is a system of care delivery most appropriate for patients with a predictable trajectory of illness and death, such as that of terminal cancer. Similar to cancer, the advancement of HF into later stages also follows known patterns as symptoms become more intense and refractory to standard treatments, leading to recurrent acute-care utilization and contributing to poor quality of life [4]. However, the symptom burden and HF classification, such as the New York Heart Association (NYHA) classification [5], are dependent on a patient's fluid overload status and can wax and wane unpredictably. Regardless, the symptom burden in HF, including dyspnea, pain, anxiety, fatigue, and depression, can equal or exceed that in cancer populations [6]. Yet, evidence shows that HF patients have suboptimal access to and provision of PC and hospice [7][8][9][10][11].
In 2015, the National Academy of Medicine (formerly called the Institute of Medicine) issued recommendations to improve advance care planning and increase access to PC for all seriously ill patients [12,13]. Subsequently, leading professional societies including the American College of Cardiology, American Heart Association, Heart Failure Society of America, and the International Society for Heart and Lung Transplantation published clinical guidelines recommending improved access to hospice and PC for patients with advanced HF [14][15][16][17][18][19][20]. Likewise, the American Society of Clinical Oncology, the National Comprehensive Cancer Network (NCCN), and the National Academy of Medicine have endorsed timely PC referral for cancer patients [21][22][23]. However, despite guidelines recommending the inclusion of PC, there are limited data offering guidance on PC in patients with a dual diagnosis of cancer and HF. Therefore, we conducted this systematic literature review with the following aims: (1) To identify existing criteria for referral to and early integration of PC in the management strategies for patients with cancer and patients with HF. (2) To identify assessments of outcomes of PC intervention that overlap between patients with cancer and patients with HF.
This review will provide baseline information to define best practices for referral to and successful delivery of PC to patients living with cancer and HF.

Study design and search strategy
We performed a systematic search of the literature for studies assessing criteria for and outcomes of PC referral in both HF and cancer. We searched Ovid Medline, Ovid Embase, Cochrane Library, and Web of Science from January 2009 to September 2020. Search structures, subject headings, and keywords were tailored to each database by a medical research librarian (KJK) specializing in systematic reviews. Case reports, animal studies, and articles in languages other than English were excluded, without any other restrictions by study type. Search strings included MeSH and Emtree subject headings, which included: "heart failure", "neoplasms", "hospice care", and "palliative care". Keyword searching was used to retrieve articles with related terms and phrases in the titles and abstracts.

Study selection
Our initial search retrieved 8,647 citations, and after removal of duplicates, 5,482 citations remained for review, comprising 4,180 articles for cancer and 1,302 articles for HF. Citations were independently screened by two investigators (APF, AP) by using the titles and abstracts of the articles to identify potentially relevant studies. Disagreements were resolved by consensus and by seeking the opinion of a third reviewer (NLP). Studies that passed the title/ abstract review were retrieved for full-text review. The two screening investigators (APF, NLP) then independently screened the remaining full-text articles. Disagreements were resolved by consensus and by seeking the opinion of a third reviewer (EB). After final review, 16 studies on cancer and 14 studies on HF were included. A PRISMA flow diagram ( Figure 1) shows the entire review process from the original search to the final selection of studies.

Statistical methods
The main outcome measures for this systematic literature review were criteria for and outcomes of referral to PC for patients with diagnoses of cancer and HF. Because of the heterogeneity of study designs, participants, interventions, and reported outcomes, meta-analytical statistical comparison was not possible. Therefore, we focused on describing the studies, their results, and their limitations via a qualitative synthesis.

Results
The studies selected for inclusion in the review were analyzed for risk of bias to understand and appraise their strengths and weaknesses, and results are outlined in Table 1 (cancer) and Table 2 (heart failure).

Referral criteria
Four studies [26,30,33,34] identified and characterized the PC needs of cancer patients using questionnaires and assessment instruments. Sanders et al. (2010) reported that patients' greatest PC needs were in the physical and daily living domain, followed by psychological needs, health system and informational needs, and patient care support needs. The most common unmet need was a lack of energy and tiredness (75%). Grudzen    Hui 2020 Caraceni 2020 Gemmel 2020 Hansen 2020 Study Design

Outcomes
Of the eight studies that explored the outcomes of PC in patients with cancer, two randomized controlled trials [28,38] evaluated the benefit of early versus delayed PC referral on patient reported outcomes including quality of life (QOL), symptom impact, mood, survival and resource use. In the study of 151 patients with newly diagnosed metastatic non-small cell lung cancer, patients assigned to early PC had a better quality of life than did patients assigned to standard care [28]. In addition, even though there were fewer patients in the early PC group than in the standard care group that received aggressive end-of-life care (33% vs. 54%, P = 0.05), median survival was longer among patients receiving early palliative care (11.6 months vs. 8.9 months, P = 0.02). Conversely, in another study comparing the effect of early versus delayed PC referral in 207 patients with advanced cancer, patient-reported outcomes (quality of life, symptom impact, mood, 1year survival), and resource use were not significantly different between patients with early referral than those with delayed referral [38].   [24]. Similarly, using the NCCN guidelines' criteria as a trigger for PC referral resulted in a significant increase in patients' access to PC service, and PC referral also appeared to occur earlier in the course of the disease as a result [35,36]. However, triggered PC consultation had minimal impact on hospice utilization, cost of care, survival, patient-reported symptoms, and patient satisfaction [23]. In addition, using the standardized criteria for automatic PC consultation did not significantly change length of stay (P = 0.15) or use of the intensive care unit (P = 0.11) [25], or hospital costs [27].

Heart failure
A total of 292,699 patients were included in the 14 studies of HF and PC (Table 4). Eight studies were retrospective, and six were prospective, with two of the included studies evaluating different data from the same randomized controlled trial of PC intervention. Eight studies looked at referral criteria only, five studies evaluated outcomes only, and one study evaluated both referral criteria and outcomes.

Referral criteria
The nine studies that assessed potential referral criteria for PC in patients with HF looked at various factors.
Harding et al. (2009) compared characteristics of 28 admitted patients with HF between those who were appropriate for PC referral and those who were not. Patients with HF appropriate for PC referral had more previous admissions, had more multi-professional inpatient staff evaluating them, and were more likely to have a do-not-resuscitate order [43]. Other studies examined the accuracy of tools for predicting survival in HF patients, which could help guide goals-of-care discussion and PC referral. James et al. (2010) retrospectively applied the Seattle Heart Failure Model (SHFM) [44], which predicts lifespan using clinical, medication, laboratory, and intervention data, in patients admitted with HF to evaluate the accuracy of this model and its potential to identify patients who would benefit most from PC referral. The authors concluded that post-intervention SHFM scores could help identify patients for PC referral [45].  [41] and Palliative Performance Scale [48]) and two validated HF assessments (NYHA functional class [5] and Kansas City Cardiomyopathy Questionnaire [KCCQ] [49,50]) and found significant correlation between the PC and HF assessments (P < 0.0001 for each PC assessment compared with NYHA class and compared with the KCCQ). The authors proposed that since the ESAS and Palliative Performance Scale showed good correlation with traditional HF scores, they could be useful in assessing HF patients for PC referral [51]. In a retrospective single-center study of all patients admitted for HF between 2005 and 2010, Greener et al. (2014) found that 6.2% were referred to PC, and multivariable logistic regression analysis found several predictors of PC referral, including previous HFrelated hospitalizations, admission to the intensive care unit, older age, married status, and higher severity of illness. The authors speculated that being married was a predictor for PC referral because PC services provide resources not only for the patient but also for family members and caretakers [52]. Campbell et al. (2018) performed a prospective observational study of 272 patients and found that those needing a PC specialist were  To develop a definition of specialized PC needs and assess outcomes of those Prospective, observational 27% of patients had specialized PC needs, and these patients were older (P = 0.041); had lower SBP (P = 0.018), more severe NYHA class (P = 0.031), lower scores on AKPS who received specialized PC and NAT-PD-HF (P < 0.001 and 0.008), and higher Zarit Burden Interview severity (P < 0.001); and were more likely to have a history of myocardial infarction (P = 0.004) and a history of diabetes (P = 0.029).
Kane et al.   [50]. However, in contrast to the previous studies presented, patients needing a PC specialist were younger (P = 0.076) and did not differ in number of comorbidities [53]. Kane et al. (2018) evaluated recruitment strategies for 372 patients with HF to undergo a PC needs assessment and ultimately compared 25 patients who completed the PC intervention. The authors found that using NYHA class as a criterion for referral to PC was problematic for two main reasons: (1) NYHA class can change owing to changes in volume status, so a proportion of patients with NYHA class II may have PC needs but momentarily appear too healthy for PC. (2) Assessment of NYHA class can be subjective, as seen in differences in application of NYHA class between sites included in the study. The authors recommended using indicators other than NYHA class for PC referral, as done in the 2016 European Society of Cardiology definition of HF [54]. Finally, Roch et al. (2020) evaluated an integrated PC outcome scale, which identified relevant symptoms for PC referral in 75% of patients and was determined by a vast majority of patients (95%) to be an easy tool to understand. The study highlighted the importance of using tools accepted by both the patients and the providers when assessing PC referral [55].

Outcomes
A total of 287,595 patients were included in the six studies evaluating outcomes after PC referral. In a retrospective study of resource use near the end of life among 229,543 Medicare beneficiaries with HF, Unroe et al. (2011) found that hospice referral increased from 19% to almost 40% from 2000 to 2007 however, costs remained elevated, and use of other services such as inpatient hospitalization and echocardiograms did not decrease. Many patients had short hospice stays, with 37% having stays less than 7 days, and the authors surmised that this short duration may have prevented patients and families from receiving the full benefit of hospice services, owing to the late referral [56]. Kheirbek et al. (2015) matched 179 hospice-referred patients with propensity-matched hospice-eligible patients and found that readmission rates were lower for the hospicereferred patients up to 6 months after discharge, including 30-day readmission. However, one possible explanation for the lower re-admission rate was the fact that over 40% of patients in the hospice-referred group died in the first 30 days after discharge, suggesting, again as the aforementioned study also stated, that PC referral occurred too late [57].
In the only randomized trial of PC intervention in HF patients, the primary endpoint for 150 patients was quality-of-life change at 6 months as assessed by the KCCQ and Functional Assessment of Chronic Illness Therapy-Palliative Care scale (FACIT-Pal) [58]. Patients with PC referral had statistically significant improvements in quality of life (KCCQ: P = 0.030, FACIT-Pal: P = 0.035) compared with those with usual care; however, mortality was not affected and, as in other studies in our analysis, re-hospitalization was not affected [59]. A secondary analysis of the same trial evaluated differences in quality of life between men and women and found that men had significant improvement in KCCQ scores at 6 months, whereas women did not (P = 0.047 versus P = 0.39). Campbell et al. (2018), in addition to assessing predictors of needing specialist PC, also prospectively evaluated outcomes of patients with HF. Only 24% of patients meeting criteria for needing specialist PC actually received PC. The patients meeting these criteria had

Discussion
Cardio-oncology is already a multidisciplinary specialty with unique considerations for patient care when cancer coexists with cardiovascular disease, including HF. The added complexities of PC needs make this patient group a complicated one to treat. Many studies have evaluated PC in patients with cancer or HF, but a dearth of evidence exists regarding patients with both. This systematic review reveals areas of overlap and potential improvement for identifying PC referral criteria and assessing outcomes of PC intervention in these patients. Cancer and HF share similarities in their patientreported symptoms, quality of life, symptom burden, social support needs, readmission rates, and mortality. Symptoms evaluated in questionnaires such as the ESAS for cancer and the KCCQ for HF commonly include fatigue and dyspnea assessments. This overlap may be a reason for the significant correlation found by Ezekowitz et al. (2011) between the ESAS and KCCQ assessments (P < 0.0001). In addition to quantifying the severity of these symptoms, the questionnaires also quantify the degree to which the patient's quality of life is affected by the symptoms. Importantly, ESAS and KCCQ are patient-reported symptoms, as opposed to provider assessments, and patients are often more concerned with how they feel than with etiology or pathogenesis. Providers from both oncology and cardiology can address patient symptoms with PC intervention, regardless of whether symptoms are due to cancer or to HF. This multidisciplinary relevance is the strength of using patient-reported outcomes and there has been an increase in studies validating their use for various cancer and HF subtypes. Other symptoms that have been identified in both cancer and HF include anxiety, distress, delirium, and depression. Future studies of PC in patients with both cancer and HF should include quantification of all of these symptoms and their impact on quality of life.
One often-overlooked strength of PC intervention is the social support for caregivers in addition to the patient. The assessment of caregiver needs was addressed more in the included studies of cancer, while only one of the HF studies assessed this need. This difference may be due to the higher number of citations for PC with cancer compared to citations for PC with HF. Another possible explanation is the understanding and impression of a cancer diagnosis on patients and their families, compared with that of a diagnosis of HF. Many patients and family members associate cancer with a high risk of death; however, HF has worse mortality than many cancers but does not have the same stigma of death. Another factor is the predictability and duration of cancer treatment. Family members can plan for expected declines after chemotherapy or radiation and allocate the time needed to care for the patient. Therefore, increased use of caregiver-needs assessments are needed in the evaluation of patients with HF for PC.
With the increasing incidence of cardiotoxicity from anticancer agents that can result in HF, a collaboration between oncology and cardiology is paramount for the integration of PC to manage the complex issues in cardio-oncology patients. Although early referral to PC has been shown to improve outcomes, yet, PC referrals remain delayed because of a lack of criteria on who should be referred or the optimal timing for referral. To facilitate the incorporation of PC in the care of patients with cancer and HF, a set of criteria that address both cancer and HF are necessary. Table 5 shows a list of the referral criteria important for PC intervention in patients with cancer and patients with HF and identifies areas where there is overlap between cancer and HF. The next step would be to conduct a Delphi study on a combination of these proposed criteria to develop a consensus among the cardio-oncology experts on a list of criteria for PC referral for patients with cancer and HF. These criteria, if validated, could provide guidance for identification of patients suitable for referral to PC, and could help streamline and standardize clinical practice, research and health care resources for this increasing number of patients.
Common outcome measures between PC intervention for HF and cancer include quality-of-life assessments through patient-reported outcomes, readmission rates, and mortality. As observed in the use of symptom and quality-of-life questionnaires for referral to PC, there is overlap between cancer and HF patients in the use of these assessments as outcomes. Also, in both HF and cancer, readmission rates and mortality are used as significant outcomes to evaluate the efficacy of PC intervention. Mortality is a difficult measure for assessing PC efficacy, as aggressive life-saving measures will often not be pursued after PC referral, a choice that may contribute to early mortality. Furthermore, as highlighted in studies from this review, if PC referral occurs too late, the full benefit of PC services is not realized, as patients in one study passed away for an average of 7 days after referral. The outcomes of PC are thus tied with the timing of referral. Furthermore, the symptom assessment tools have limitations in their prediction of lifespan often overestimating or underestimating this important factor. Therefore, part of optimizing outcomes is assessing the time-based criteria for referral noted in Table 5. Further research is needed to improve individual lifespan prediction after a diagnosis of cancer and HF, which will then improve outcomes by enabling appropriate timing of PC referral.
Increasing awareness and recognition of PC as an important consideration for patients with cancer and HF is evident from the increased number of citations on this topic every year ( Figure 2). Still, cancer citations outnumber those of HF 2 to 1, and it is clear that more progress is needed to improve utilization of PC in patients with HF. At the time of this review, there is only one randomized controlled trial comparing the use of PC versus usual care in patients with HF. Even more understudied is the niche field of cardio-oncology involving PC referral in patients with both cancer and HF. More studies are needed to better delineate PC in this specialized patient population.

Limitations
The searches were limited to English only. Inclusion of articles in languages other than English may have broadened our results, but translation of these articles was not feasible. The limitations of this review were the lack of a quantitative statistical meta-analytic comparison of studies because of the heterogeneity of the study designs, participants, interventions, and reported outcome measures.

Conclusion
The complexities of the multiple issues confronting patients diagnosed with cancer and concurrent HF present challenges in decision-making regarding PC initiation. The multiple comorbidities of this population and the unpredictable illness trajectory of HF add to the complexity of prognostication, particularly with the potential for sudden cardiac death. This systematic literature review provides evidenced-based data to inform the development of criteria for PC referral for patients with cancer and concurrent HF, being mindful that referrals should not rely only on end-of-life or terminal stages. Integrating PC in cardio-oncology, particularly in the management of HF in patients with cancer, as early as at diagnosis, will enable patients, family members, and healthcare professionals to make informed decisions about various treatments and end-of-life care and provide an opportunity for patients to participate in the decisions about when and where they will spend their final days. Additional research is needed to develop and validate clinically useful criteria for PC referral to prospectively identify cancer patients with a concurrent diagnosis of HF patients who may most benefit from PC referral.