A hospital-based Palliative Care Pathway for patients with advanced cancer:Bridging the gap between science and practice

Palliative care aims to improve the quality of life of patients and their families dealing with the problems associated with an incurable disease, such as advanced cancer1. Palliative care includes shared decision making (SDM) and advance care planning (ACP), to facilitate the alignment of care to the current and future needs and preferences of patients. Timely integration of palliative care into oncology care is important, to be able to discuss, fulfill and coordinate patients' care needs and preferences in a timely manner before a person loses capacity. The surprise question is often recommended as a tool to identify patients who may be in the final stage of life and thus might benefit from tailored palliative care. A multidisciplinary team approach combined with the use of standardised care pathways has been considered an essential part of such integration. Because oncology and palliative care are increasingly provided in the outpatient setting, various health care professionals, including hospital staff, general practitioners and district nurses, need to collaborate and exchange information. Nevertheless, hospital admissions in the last phase of life are frequent and a substantial number of patients die in the hospital, although most people prefer dying out of hospital. In the Netherlands, palliative care is mostly provided by non-specialised healthcare professionals, who should have basic knowledge and skills in palliative care. When required, they can seek support from a palliative care specialist. In the Maasstad Hospital, a multidisciplinary group developed a digital standardised 'Palliative Care Pathway' (PCP) for patients with advanced, incurable cancer, to support healthcare professionals in the hospital with the timely initiation and provision of palliative care alongside tumour-specific care. Indications to start the PCP are: a negative answer to the surprise question (“Would you be surprised if this patient died within the next 12 months?”); deterioration of a patient’s performance status; a severe complication of medical treatment; the patient’s wish to stop all medical treatments; and/or a situation where no more anticancer treatment options are available. After opening the PCP, various prompts guide the physician to explore patients’ needs in all palliative care dimensions: physical, psychosocial and/or spiritual. Furthermore, the PCP facilitates the documentation of bad-news and ACP conversations, involvement of family and relatives and coordination of multidisciplinary care.The overall aim of this thesis is to contribute to the quality and integration of palliative care and oncology care by evaluating hospital care at the end of life and the implementation of a digital standardised PCP. The research questions addressed in this thesis are:1) Why are patients with advanced cancer admitted to the hospital in the last phase of life and what happens during such hospitalisations?2) What are the effects of implementation of a standardised digital PCP for patients with advanced cancer on the process of care and the experiences of care of their bereaved relatives? 3) To what extent do hospital discharge letters concerning patients with a limited life expectancy include information about patient’s poor prognosis and preferences for treatment and care? 4) How can 1-year mortality in patients with advanced cancer be predicted?OUTLINE OF THIS THESISChapter 2 of this thesis includes a retrospective medical record review study to gain insight why patients with advanced cancer are hospitalised at the end of life, so that we better understand to what extent they can be prevented. Chapter 3, 4 and 5 present the pre- and post-intervention study of the effects of implementation of the PCP in the Maasstad Hospital on care processes and adresses a questionnaire study of berevead relatives’ satisfaction with hospital care. Chapter 6 describes a focus group study exploring the experiences of healthcare professionals using the PCP. In a retrospective medical record review presented in Chapter 7, we studied the quality of hospital discharge letters concerning patients with a limited life expectancy. Chapter 8 describes a multicenter prospective study on the development of a clinical model and nomogram to predict 1-year mortality for patients with advanced cancer. The thesis concludes with a discussion of and reflection on the main findings in Chapter 9. A Dutch summary of this thesis is provided in Chapter 10.Chapter 9 summarizes the main findings of the studies conducted, discusses some methodological considerations, and extensive reflections are provided on a number of topics. It first discusses the significance of integrating palliative care into oncology care, in which advance care planning is an important component. Timely initiation of palliative care seems to be a global challenge. Using the "surprise question" as a tool to timely identify patients' palliative care needs and initiate the PCP was not found to be very effective in our study. The PCP was initiated on average about a month before death, whereas we aimed for a period of several months to a year with the 'surprise question'. The implementation of the PCP may well have generally raised awareness among health care providers of patients' impending death and the need for palliative care, and could support discussions about patients' preferences and appropriate decision-making in the last phase of life, even if it is not actually used for individual patients. Implementation of the PCP in daily practice was complex and challenging. Reflection on the strategy employed in implementing the PCP is given from the concept of " Implementation Science." General conclusions are then drawn from the studies described and recommendations for daily practice and future research follow.<br/

Tumor-agnostic ctDNA levels by mFAST-SeqS in first-line HR-positive, HER2 negative metastatic breast cancer patients as a biomarker for survival

This prospective cohort study reports aneuploidy score by mFast-SeqS as a strong prognostic marker in MBC patients. mFAST-SeqS is an affordable and easily implementable method for the assessment of total ctDNA levels and, as such, provides an alternative prognostic tool. One mixed cohort (cohort A, n = 45) starting any type of treatment in any line of therapy and one larger cohort (cohort B, n = 129) consisting of patients starting aromatase inhibitors (AI) as first-line therapy were used. mFAST-SeqS was performed using plasma of blood in which CTCs (CellSearch) were enumerated. The resulting aneuploidy score was correlated with categorized CTC count and associated with outcome. The aneuploidy score was significantly correlated with CTC count, but discordance was observed in 31.6% when applying cut-offs of 5. In both cohorts, aneuploidy score was a significant prognostic marker for both PFS and OS. In the Cox regression models, the HR for aneuploidy score for PFS was 2.52 (95% CI: 1.56–4.07), and the HR for OS was 2.37 (95% CI: 1.36–4.14). Results presented here warrant further investigations into the clinical utility of this marker in MBC patients.</p

The effect of (neo)adjuvant chemotherapy on long-term survival outcomes in patients with invasive lobular breast cancer treated with endocrine therapy:A retrospective cohort study

Background: Despite histological and molecular differences between invasive lobular carcinoma (ILC) and invasive carcinoma of no special type, according to national treatment guidelines no distinction is made regarding the use of (neo)adjuvant chemotherapy. Studies on the long-term outcome of chemotherapy in patients with ILC are scarce and show inconclusive results. Methods:All patients with estrogen receptor (ER)–positive, human epidermal growth factor receptor 2 (HER2)–negative ILC with an indication for chemotherapy treated with adjuvant endocrine therapy were selected from the Erasmus Medical Center Breast Cancer database. Cox proportional hazards models were used to estimate the effect of chemotherapy on recurrence-free survival (RFS), breast cancer–specific survival (BCSS), and overall survival (OS). Results: A total of 520 patients were selected, of whom 379 were treated with chemotherapy and 141 were not. Patients in the chemotherapy group were younger (51 vs. 61 years old; p &lt;.001), had a higher T status (T3+, 33% vs. 14%; p &lt;.001), and more often had lymph node involvement (80% vs. 49%; p &lt;.001) in comparison to the no-chemotherapy group. After adjusting for confounders, chemotherapy treatment was not associated with better RFS (hazard ratio [HR], 1.20; 95% confidence interval [CI], 0.63–2.31), BCSS (HR, 1.24; 95% CI, 0.60–2.58), or OS (HR, 0.97; 95% CI, 0.56–1.66). This was also reflected by adjusted Cox survival curves in the chemotherapy versus no-chemotherapy group for RFS (75% vs. 79%), BCSS (80% vs. 84%), and OS (72% vs. 71%). Conclusions:Chemotherapy is not associated with improved RFS, BCSS, or OS for patients with ER+/HER2− ILC treated with adjuvant endocrine therapy and with an indication for chemotherapy.</p

Spiritual well-being and associated factors in Dutch patients with advanced cancer

CONTEXT: Palliative care aims to support patients' spiritual needs with the intention of promoting their spiritual well-being (SWB), an important dimension of quality of life. SWB is one of the less-studied dimensions of QoL, particularly in a secular country such as the Netherlands. OBJECTIVES: In this study we aimed to get a better understanding of SWB in Dutch patients with advanced cancer. We therefore examined its prominence and associated factors. METHODS: We used the baseline data of a cohort study on experienced quality of care and quality of life (eQuiPe study), which included 1,103 patients with advanced cancer. In addition to sociodemographic and religious/spiritual characteristics, study measures comprised the SWB subscales Meaning, Peace, and Faith of the revised FACIT-Sp-12, spiritual problems and needs (PNPCsv), quality of life (EORTC-QLQ-C30) and satisfaction with healthcare professionals' interpersonal skills (INPATSAT-32). RESULTS: On average, patients experienced quite a bit of Meaning (8.9, SD 2.3), a little bit to somewhat Peace (6.8, SD 2.7), and very low levels of Faith (2.9, SD 3.7). Two-thirds (71%) of patients reported one or more spiritual problems, for which the majority (54%) wanted to receive attention. In the final multivariable models, only a few factors were associated with SWB, such as greater spiritual needs with lower levels of Meaning and Peace. CONCLUSION: Dutch patients with advanced cancer experience medium to low levels of Meaning, Peace, and Faith. More attention for their SWB is warranted

The effect of (neo)adjuvant chemotherapy on long-term survival outcomes in patients with invasive lobular breast cancer treated with endocrine therapy:A retrospective cohort study

Background: Despite histological and molecular differences between invasive lobular carcinoma (ILC) and invasive carcinoma of no special type, according to national treatment guidelines no distinction is made regarding the use of (neo)adjuvant chemotherapy. Studies on the long-term outcome of chemotherapy in patients with ILC are scarce and show inconclusive results. Methods:All patients with estrogen receptor (ER)–positive, human epidermal growth factor receptor 2 (HER2)–negative ILC with an indication for chemotherapy treated with adjuvant endocrine therapy were selected from the Erasmus Medical Center Breast Cancer database. Cox proportional hazards models were used to estimate the effect of chemotherapy on recurrence-free survival (RFS), breast cancer–specific survival (BCSS), and overall survival (OS). Results: A total of 520 patients were selected, of whom 379 were treated with chemotherapy and 141 were not. Patients in the chemotherapy group were younger (51 vs. 61 years old; p &lt;.001), had a higher T status (T3+, 33% vs. 14%; p &lt;.001), and more often had lymph node involvement (80% vs. 49%; p &lt;.001) in comparison to the no-chemotherapy group. After adjusting for confounders, chemotherapy treatment was not associated with better RFS (hazard ratio [HR], 1.20; 95% confidence interval [CI], 0.63–2.31), BCSS (HR, 1.24; 95% CI, 0.60–2.58), or OS (HR, 0.97; 95% CI, 0.56–1.66). This was also reflected by adjusted Cox survival curves in the chemotherapy versus no-chemotherapy group for RFS (75% vs. 79%), BCSS (80% vs. 84%), and OS (72% vs. 71%). Conclusions:Chemotherapy is not associated with improved RFS, BCSS, or OS for patients with ER+/HER2− ILC treated with adjuvant endocrine therapy and with an indication for chemotherapy.</p

Real-world palbociclib effectiveness in patients with metastatic breast cancer: Focus on neutropenia-related treatment modification strategies and clinical outcomes

INTRODUCTION: In addition to clinical trials, real-world data is needed to verify the effectiveness of the CDK 4/6 inhibitor palbociclib. The primary aim was to examine real-world variation in treatment modification strategies for neutropenia and its relation to progression-free survival (PFS). The secondary aim was to assess if there is a gap between real-world and clinical trial outcomes. MATERIALS AND METHODS: In this multicenter, retrospective observational cohort study 229 patients were analyzed who started palbociclib and fulvestrant as second- or later-line therapy for HR-positive, HER2-negative metastatic breast cancer in the Santeon hospital group in the Netherlands between September 2016 and December 2019. Data were manually retrieved from patients' electronic medical records. PFS was examined using the Kaplan-Meier method to compare neutropenia-related treatment modification strategies within the first three months after neutropenia grade 3 - 4 occurred, as well as patients' eligibility to have participated in the PALOMA-3 clinical trial or not. RESULTS: Even though treatment modification strategies differed from those in PALOMA-3 (dose interruptions: 26 vs 54%, cycle delays: 54 vs 36%, and dose reductions: 39 vs 34%), these did not influence PFS. Patients who were PALOMA-3 ineligible experienced a shorter median PFS than those who were eligible (10.2 vs. 14.1 months; HR 1.52; 95% CI 1.12 - 2.07). An overall longer median PFS was found compared to PALOMA-3 (11.6 vs. 9.5 months; HR 0.70; 95% CI 0.54 - 0.90). CONCLUSION: This study suggests no impact of neutropenia-related treatment modifications on PFS and confirms inferior outcomes outside clinical trial eligibility

The association between palliative care team consultation and hospital costs for patients with advanced cancer: An observational study in 12 Dutch hospitals

Background: Early palliative care team consultation has been shown to reduce costs of hospital care. The objective of this study was to investigate the association between palliative care team (PCT) consultation and the content and costs of hospital care in patients with advanced cancer. Material and Methods: A prospective, observational study was conducted in 12 Dutch hospitals.

The OCT2/MATE1 Interaction Between Trifluridine, Metformin and Cimetidine:A Crossover Pharmacokinetic Study

Background and Objectives: Trifluridine/tipiracil, registered for the treatment of patients with metastatic gastric and colorectal cancer, is a substrate and inhibitor for the organic cation transporter 2 (OCT2) and the multidrug and toxin extrusion protein 1 (MATE1), which raises the potential for drug–drug interactions with other OCT2/MATE1 modulators. Therefore, we prospectively examined the effect of an OCT2/MATE1 inhibitor (cimetidine) and substrate (metformin) on the pharmacokinetics of trifluridine. Methods: In this three-phase crossover study, patients with metastatic colorectal or gastric cancer were sequentially treated with trifluridine/tipiracil alone (phase A), trifluridine/tipiracil concomitant with metformin (phase B) and trifluridine/tipiracil concomitant with cimetidine (phase C). The primary endpoint was the relative difference in exposure of trifluridine assessed by the area under the curve from timepoint zero to infinity. A &gt; 30% change in exposure was considered clinically relevant. A p-value of &lt; 0.025 was considered significant because of a Bonferroni correction. Results: Eighteen patients were included in the analysis. Metformin did not significantly alter the exposure to trifluridine (− 12.6%; 97.5% confidence interval − 25.0, 1.8; p = 0.045). Cimetidine did alter the exposure to trifluridine significantly (+ 18.0%; 97.5% confidence interval 4.5, 33.3; p = 0.004), but this increase did not meet our threshold for clinical relevance. Metformin trough concentrations were not influenced by trifluridine/tipiracil. Conclusions: Our result suggests that the OCT2/MATE1 modulators cimetidine and metformin can be co-administered with trifluridine/tipiracil without clinically relevant effects on drug exposure. Clinical Trial Registration: NL8067 (registered 04-10-2019).</p

Open communication between patients and relatives about illness & death in advanced cancer—results of the eQuiPe Study

Objective: To assess the degree of openness of communication about illness and death between patients with advanced cancer and their relatives during the last three months of the patient’s life, and its association with relatives’ characteristics and bereavement distress. Methods: We used data from bereaved relatives of patients with advanced cancer from the prospective, longitudinal, multicenter, observational eQuipe study. Univariate and multivariable linear regression analyses were used to assess the association between the degree of openness of communication (measured using the validated Caregivers’ Communication with patients about Illness and Death scale), the a priori defined characteristics of the relatives, and the degree of bereavement distress (measured using the Impact of Event Scale). Results: A total of 160 bereaved relatives were included in the analysis. The average degree of open communication about illness and death between patients with advanced cancer and their relatives was 3.86 on a scale of 1 to 5 (SE=0.08). A higher degree of open communication was associated with a lower degree of bereavement distress (p=0.003). No associations were found between the degree of open communication and the relatives’ age (p=0.745), gender (p=0.196), level of education (p>0.773), (religious) worldview (p=0.435), type of relationship with the patient (p>0.548), or level of emotional functioning before the patient’s death (p=0.075). Conclusions: Open communication about illness and death between patients and relatives seems to be important, as it is associated with a lower degree of bereavement distress. Healthcare professionals can play an important role in encouraging the dialogue. However, it is important to keep in mind that some people not feel comfortable talking about illness and death

Perceptions of involvement in advance care planning and emotional functioning in patients with advanced cancer

Purpose: Advance Care Planning (ACP) is positively associated with the quality of care, but its impact on emotional functioning is ambiguous. This study investigated the association between perceptions of ACP involvement and emotional functioning in patients with advanced cancer. Methods: This study analyzed baseline data of 1,001 patients of the eQuiPe study, a prospective, longitudinal, multicenter, observational study on quality of care and quality of life in patients with advanced cancer in the Netherlands. Patients with metastatic solid cancer were asked to participate between November 2017 and January 2020. Patients’ perceptions of ACP involvement were measured by three self-administered statements. Emotional functioning was measured by the EORTC-QLQ-C30. A linear multivariable regression analysis was performed while taking gender, age, migrant background, education, marital status, and symptom burden into account. Results: The majority of patients (87%) reported that they were as much involved as they wanted to be in decisions about their future medical treatment and care. Most patients felt that their relatives (81%) and physicians (75%) were familiar with their preferences for future medical treatment and care. A positive association was found between patients’ perceptions of ACP involvement and their emotional functioning (b=0.162, p<0.001, 95%CI[0.095;0.229]) while controlling for relevant confounders. Conclusions: Perceptions of involvement in ACP are positively associated with emotional functioning in patients with advanced cancer. Future studies are needed to further investigate the effect of ACP on emotional functioning. Trial registration number: NTR6584 Date of registration: 30 June 2017 Implications for Cancer Survivors: Patients’ emotional functioning might improve from routine discussions regarding goals of future care. Therefore, integration of ACP into palliative might be promising