What is known about palliative care in adult patients with allogeneic stem cell transplantation (allo-SCT)?

Patients undergoing allogeneic stem cell transplantation (allo-SCT) are given a real chance of cure, but at the same time are confronted with a considerable risk of mortality and of severe long-term impediments. This narrative, non-systematic literature review aims to describe the supportive and palliative care needs of allo-SCT recipients, including long-term survivors or those relapsing or dying after transplantation. It also evaluates the feasibility and effectivity of integrating palliative care early in transplant procedures. In this appraisal of available literature, the main findings relate to symptoms like fatigue and psychological distress, which appear to be very common in the whole allo-SCT trajectory and might even persist many years post-transplantation. Chronic GvHD has a major negative impact on quality of life. Overall, there is a paucity of research on further issues in the context of allo-SCT, like the distress related to the frequently unpredictable post-transplant trajectory and prognosis, as well as the end-of-life phase. First randomized controlled results support the effectiveness of early integration of specialized palliative care expertise into transplant algorithms. Barriers to this implementation are discussed.


Introduction
The long-term survival after allogeneic hematopoietic stem cell transplantation (allo-SCT) has been increasing, which is mostly attributable to continuous advancements in procedural aspects and supportive measures [1][2][3]. Despite these improvements, the overall mortality associated with allo-SCT remains high. The 5-year survival after allo-SCT, all diagnoses included, is about 50% [4]. Complications of the allo-SCT often lead to severe symptomatology, requiring optimal supportive and palliative management.
Palliative care aims to improve "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" [5]. Relieving symptoms and managing other causes of suffering in cancer patients is mainly the task of oncologists and primary care teams in the sense of primary palliative care, but in complex situations, involvement of specific palliative care expertise will be necessary [6][7][8]. The early integration of such specialist palliative care into concepts of cancer therapy has become integral part of standard cancer care as recommended in several oncology and palliative care guidelines [6,[8][9][10][11]. Mounting evidence attests the effectiveness of early specialist palliative care in patients with solid tumors in the control of symptom intensity and with positive impacts on quality of life [6,8,9,12,13].
In contrast to solid cancers, specialist palliative care services are less frequently used in patients with hematological Steffen T. Simon and Anne Pralong contributed equally to this work. malignancies [14]. These patients receive more invasive therapies, even until shortly before death and are less likely to be informed about near death [14][15][16]. These facts from clinical practice are reflected in the current state of research in this area. There are few prospective studies that investigated the effect of early-integrated palliative care into the therapeutic algorithms in hematology [17,18], in particular in allo-SCT [19], although recent results from randomized controlled trials indicate growing interest and research activity in that field [20][21][22].
Particularly recipients and survivors of an allo-SCT deserve special attention, because of the high morbidity and mortality associated with this modality. There is a high need to best identify and manage the many unmet needs in the field of supportive and palliative care during the whole transplant trajectory. In this non-systematic review, we aim to provide an overview on the current literature and state of the art on supportive and palliative care in patients with allo-SCT, which includes (1) symptoms, psychosocial distress, quality of life, burden related to the unpredictable illness trajectory and prognosis, issues in the last phase of life, support of family caregivers and (2) the integration of specialist palliative care services into transplant algorithms. For this purpose, we conducted a non-systematic search in the database MEDLINE (via PubMed), combining search terms on allo-SCT and on palliative care, psycho-oncology, uncertainty, fear of recurrence, or death anxiety. Further publications were identified by cross-referencing from publications listed in relevant studies and by citation tracking via the PubMed link for "related articles." We included (systematic) reviews as well as original research articles (presented in Table 1). We considered studies including adult patients having undergone allo-SCT and/or their informal caregivers. Reviews or primary studies on hematology or SCT in general were also included if they reported specific results on allo-SCT. Primary studies with more than two-thirds of allo-SCT participants were considered as well. In this review, we also highlight relevant research gaps.
Symptoms, which persist at least 1 year after allo-SCT compared with population norms and non-cancer comparison groups, include fatigue, sleeping disorders, pain, and sexual dysfunction [28,53,56], with fatigue being associated with female gender and younger age, as well as acute and chronic GvHD [37,54]. In a prospective multicenter study with 239 patients, fatigue was identified as the most persistent and severe symptom even 5 years after allo-SCT; it was also the most important predictor of a reduced quality of life [38]. Even if global fatigue returned to pre-transplantation levels after about 1 year and remained stable for the next 5 years, it was still significantly more prevalent than in the general population [37].
Patients with acute graft-versus-host disease (GvHD) have a higher burden of physical symptoms and inferior physical well-being [32,50]. Chronic GvHD is an important issue at long term and predicts very strongly the persistence of impaired physical functions [28,54,57].
Psychological distress is among the most prevalent symptoms in patients with allo-SCT [52][53][54]. Anxiety has been described as frequently increased especially before transplantation [40], while depression becomes prominent post-transplantation, with an increased prevalence until 10 years postallo-SCT [40,54]. Post-traumatic stress disorders (PTSD) is a major concern in about 5 to 19% of SCT survivors, independent of the kind of transplantation [21,39,54,65]. Cognitive disorders are relatively common among patients that undergo and underwent an allo-SCT, and are frequent even before the transplantation [48,49]. A cognitive decline from pre-to post-(allo-)SCT could not be demonstrated in a metaanalysis of 404 patients [58]. Compared to autologous SCT recipients, patients with allo-SCT appear to have a higher risk for long-term psychological distress, especially those with chronic GvHD [52,54]. Acute and chronic GvHD both have a negative impact on mental health [50,59].
The quality of life after transplantation has been reported to return to pre-allo-SCT levels after about 1 year [50,54,59]. Risk factors for poorer quality of life include young age, female gender, low educational level, limited social support, physical symptoms, and depression as well as acute and chronic GvHD [54]. Chronic GvHD is the major cause of impaired quality of life in allo-SCT survivors [55]. Patients with poorer quality of life have a higher risk of expressing regrets about their decision to undergo the allo-SCT procedure [33].
The effectiveness of early integration of specialist palliative care on symptom burden, psychological distress, and quality of life was examined in a randomized controlled trial (RCT) with 160 SCT recipients-to our knowledge the only one to date in the context of SCT [20,21]. The interventional group    [37], anxiety and depression [40], others [38]), PTSD [39], cancer-and-treatment-specific distress [41], and fear of recurrence [42] Global fatigue:   Abbreviations: allo-SCT, allogeneic stem cell transplantation; BL, baseline; CI, confidence interval; FC, family caregivers; GvHD, graft-versus-host disease; HRQL, health-related quality of life; ICU, intensive care unit; MAC, myeloablative conditioning; OR, odd ratio; PC, palliative care; PTSD, posttraumatic stress disorder; QoL, quality of life; RIC, reduced-intensity conditioning; RR, relative risk; SDS, symptom distress score; sign., significant allogeneic, or RIC allogeneic) with half of the patients receiving an allo-SCT. Transplant type was not found to be a mediator of the effect of the intervention. In the interventional arm, patients showed less reduction in quality of life at 2 weeks after admission, which was significant and clinically relevant (Functional Assessment of Cancer Therapy -Bone Marrow Transplantation [FACT-BMT]: mean difference between the groups −6.82 [95% CI: −13.48 to 0.16; p = 0.045]). Among secondary endpoints, at 2 weeks post-SCT, anxiety was significantly lower in the interventional group, while depression and symptom burden increased significantly less, and levels of fatigue did not differ. At 3 months post-SCT, quality of life was higher and symptoms of depression were lower in the interventional group [20]. At 6 months, the significant differences for the parameter of depression persisted and symptoms of a post-traumatic stress disorder were lower in the interventional arm [21].

Family caregivers
The impact of allo-SCT also extends to the family caregivers, who play a key role in caring for patients after discharge from the hospital [52,64]. Most of them are spouses. They experience an increased level of anxiety and symptoms of depression as well as physical symptoms like fatigue, sleep disturbances ,weight loss, and changes in marital and social life [64]. Their own burden might also have an impact on patients' outcomes, like mental health or number of hospitalizations [64]. More research is needed to better understand the interrelation between the needs of patients and their caregivers, and to develop targeted interventions. First results of psychological interventions are promising [66,67]. The early integration of specialized palliative care in standard allo-SCT procedures might also positively affect caregivers' outcomes, as shown in the mentioned RCT [20]: caregivers of patients in the intervention group had a significantly smaller increase in depression at 2 weeks as compared to caregivers of patients in the standard care arm; however, no significant differences in quality of life or anxiety were found at that time point.
Unpredictable illness trajectory and prognosis: uncertainty, fear of recurrence, and death anxiety Allo-SCT has a high potential to provide long-term remissions of the underlying hematologic disease, but it is also associated with a high mortality [1,2,4]. In this context, uncertainty, death anxiety, and fear of recurrence are further sources of distress that patients experience in the context of an allo-SCT [41,42,46].
In allo-SCT recipients, uncertainty emerges as a main cause of burden and suffering [25,26,[34][35][36]43]. In a prospective cohort of 239 patients undergoing allo-SCT, uncertainty was found to be one of the predictive factors for symptoms of post-traumatic stress disorder before, 3, and 12 months after transplantation [41]. The authors hypothesized that the high uncertainty level may be due to the complex and unpredictable nature of allo-SCT, which is in line with findings on the first descriptions of patient's uncertainty in unspecific illness situations [68][69][70]. Mishel, for instance, delineated four forms of uncertainty in a general context of illness: ambiguity regarding the state of the illness, complexity of treatment, lack of information, and unpredictability of prognosis [70]. Uncertainty in advanced illnesses like metastatic cancers has been addressed by various authors [68,71,72]. They confirm Mishel's four forms of uncertainty, with complexity and unpredictability of illness being the most relevant factors at the end of life [68]. However, the exact components of uncertainty in the allo-SCT population and the ways to communicate and to manage still need to be explored [69,73].
Fear of recurrence has been defined as the "fear, worry or concern relating to the possibility that cancer will come back or progress" [74]. Although it can be considered so far as a normal response to a cancer diagnosis, it may lead in some cases to dysfunctions like difficulties in sleeping and anxiety as well as to a decreased quality of life [75]. It therefore requires special consideration in clinical practice. The few research findings available for patients after allo-SCT indicate that about a third of them suffer from fear of recurrence [42,45].
Fear of death is another important stress factor in allo-SCT [46]. However, it has hardly been explored to date and data from patients undergoing SCT are missing so far. A survey with 109 patients highlights fear of death as one of the main components of stress in allo-SCT, among other factors like change of life, side effects, or family concerns [46]. Prevalence rates for fear of death in patients with advanced cancer range from 30 to 80% [76,77]. In patients treated for hematologic disease with a curative intent, preoccupation with death was found to be associated with higher anxiety and depression rates as well as with reduced coping [78]. Recently, interventions addressing death anxiety were developed (overview in [79]), but do not address allo-SCT recipients specifically.
To what extent fear of recurrence, death anxiety, and uncertainty are interrelated has been addressed rather rudimentarily [80][81][82]. Raising this issue could help to better understand distress in allo-SCT recipients and to optimize current management strategies.

End-of-life care in patients with allo-SCT
When the underlying disease fails to respond to the allo-SCT modality or side effects such as infectious complications or refractory GvHD become incurable, the patient's condition often deteriorates quickly. The goal of care then needs to be adapted to focus on an effective symptom control and to improve the quality of life. Life-prolonging treatments (including blood transfusion) are often stopped at this point. After this change of goals of care from life-prolonging to end-of-life care, the time until death is often short [29][30][31].
The last phase of life, including the dying phase, has been investigated in some studies on patients with hematologic cancers [16,51,[83][84][85][86]. Their findings suggest a similar symptom burden and decline in the last 3 months of life as compared to patients with solid tumors [83,85]. For end-oflife care in patients with allo-SCT, studies are missing so far, besides two retrospective chart reviews with participants who died after allo-SCT; the patients had an elevated burden of symptoms [29,30]. Further research is necessary to explore distress and needs of patients with allo-SCT and their informal caregivers and to describe the illness trajectory in the last phase of life.

Early integration of palliative care in the standard care of patients with allo-SCT
The early integration of specialist palliative care expertise in the transplant procedure aims at improving the experience of patients and caregivers throughout the individual trajectory, irrespective of whether that involves cure, chronic comorbidity, or death. This is achieved by improving symptom control, preventing and palliating psychosocial distress, enhancing patients' and caregivers' coping, and-if death nears-by caring through the last phase of life and by supporting caregivers' bereavement [19-21, 87, 88]. This has been an emerging issue over the last years.
In general, the use of specialist palliative care services for patients with allo-SCT is rather infrequent, although it appears to have increased in recent years. A large retrospective US-American chart review of 21,458 patients hospitalized for SCT (40% with an allo-SCT) describes that 1.95% of allo-SCT recipients received specialized palliative care [44]. There was a significant increase in its use from 2008 to 2014 (annual percentage change 16.45%). Among the patients who died during hospitalization, the rate of involved palliative care services was only 33.40% [44].
Barriers resulting in the late and low rate of integration of specialist palliative care into the therapeutic algorithms in hematology have been described in general reviews on hematologic malignancies [14,55,[89][90][91]. Their results are also applicable to the specific context of allo-SCT. They describe disease-related barriers like the unpredictable course of hematologic diseases or the unclear interface between a curative and palliative stage. Subjective factors play an important role as well, e.g., the perception that palliative care refers exclusively to the last phase of life, the fear to reduce patients' hope, unrealistic expectations of patients, family members, and clinicians, or suboptimal collaborations between the disciplines of hematologists and palliative care experts [14,55,[89][90][91].
Several models of integration of specialist palliative care in (allo)-SCT have been proposed, ranging from a selective palliative care consult ordered by the transplant team to the upfront integration of palliative care specialists in routine transplant care [19,87]. However, such models of integration are implemented only in few institutions worldwide and thorough analyses of real-world clinical experiences are missing so far [19,87]. Research on the efficacy of these models is also scarce. The RCT of El-Jawahri et al. mentioned previously confirmed the effectiveness of a consultative model on improving symptoms and quality of life [20,21]. Further studies with a non-controlled prospective design supported the effectivity of other consultative models on palliative outcomes such as goals-of-care discussions, hospice referral, and keeping up hopes after talking to palliative care professionals [47,92]. There is a need for research also on other models of integration such as co-rounding, embedded models with routine inclusion of palliative care, or models for allo-SCT survivors [19].

Impact for clinical care
Integrating specialist palliative care early in the course of the allo-SCT procedure likely contributes to achieve the best possible symptom control, to help patients and caregivers to better cope with the illness and its prognosis (including distress by uncertainty, fear of recurrence, and death anxiety), and to optimize quality of life [17,19,47,55,87,88]. Strategies for an early integration should be adapted to the specific issues of transplantation, as already implemented in some few projects [20,21]. Structured interventional strategies (programs) along the whole transplant trajectory are likely to be more effective then sporadic on-demand involvements. A main issue around integrating palliative care in clinical SCT practice remains a regular contact and communication between transplant physicians and palliative care specialists in order to ensure a best possible collaboration between both disciplines. A further issue is the adequate information of patients about the advantage of integrating palliative care, even before transplantation.

Impact for research
Overall, there is a high need for further research on burden, needs, and coping of allo-SCT patients and their caregivers, regarding physical symptoms as well as psychosocial distress when facing an uncertain prognosis and death. There is also an urgent need for interventional studies evaluating the most effective strategies to integrate specialist palliative care into the allo-SCT setting. It is furthermore highly warranted to systematically assess the effect of integration of psycho-oncology, psychosocial, and supportive care services in transplant procedures on outcome parameters such as quality of life in comparison to the impact of integration of specialized palliative care.

Conclusion
During the past decades, survival of patients after allo-SCT has continually improved. Despite such better prognoses and the reduction of treatment complications, morbidity and mortality remain relatively high in this patient population. We need to better integrate palliative care into the standard care of patients with allo-SCT in order to improve symptom control, to enhance the prevention and support of psychosocial distress, and to provide best care at the end of life. Wellconducted studies around these topics are still scarce, although becoming more frequent, as far as we can judge from the results of this non-systematic review. They are urgently needed to provide best possible care and quality of life for patients undergoing an allo-SCT.
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Conflict of interest The authors declare no competing interests.
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