Clinical and Translational Oncology https://doi.org/10.1007/s12094-023-03234-1 RESEARCH ARTICLE Frequency of anticancer drug use at the end of life: a scoping review Endre Szigethy1,6 · Rosario Dorantes2 · Miguel Sugrañes3 · Meisser Madera4 · Ivan Sola5 · Gerard Urrútia5 · Xavier Bonfill5 Received: 26 March 2023 / Accepted: 25 May 2023 © The Author(s) 2023 Abstract Purpose Anticancer drug use at the end of life places potential extra burdens on patients and the healthcare system. Previ- ous articles show variability in methods and outcomes; thus, their results are not directly comparable. This scoping review describes the methods and extent of anticancer drug use at end of life. Methods Systematic searches in Medline and Embase were conducted to identify articles reporting anticancer drug use at the end of life. Results We selected 341 eligible publications, identifying key study features including timing of research, disease status, treatment schedule, treatment type, and treatment characteristics. Among the subset of 69 articles of all cancer types published within the last 5 years, we examined the frequency of anticancer drug use across various end of life periods. Conclusion This comprehensive description of publications on anticancer drug use at end of life underscores the importance of methodological factors when designing studies and comparing outcomes. Keywords Neoplasms · Anticancer agents · Terminal care · Medical overuse Introduction use of this treatment and quality of life [3, 4]. Furthermore, the potential benefits of using anticancer drugs in terminally Palliative anticancer drug use is reported to prolong sur- ill cancer patients are disputed because cancer therapy might vival and relieve disease-related symptoms for some patients threaten patients’ quality of life and even survival, and also with incurable cancer [1, 2]. Conversely, other studies have imposes a significant cost on the healthcare system. Moreo- reported a marginal impact of anticancer therapy on life ver, an increasing number of articles claim that near the end expectancy and showed an unclear relationship between the of life, anticancer treatment is associated with poorer qual- ity of life [5–7] and does not improve survival [8, 9]. In this review, the term “end of life” is used referring to final days, * Endre Szigethy weeks, months in a person’s life in which it is medically szigethy@epidy.com obvious that death is imminent or a terminal moribund state 1 cannot be prevented [10]. PhD Programme in Biomedical Research Methodology and Public Health, Universitat Autònoma de Barcelona, Anticancer drug use towards the end of life is highly prev- Barcelona, Spain alent worldwide and increasing in some countries [11]. A 2 Centre Assistencial Dr. Emili Mira, Parc de Salut Mar, Santa single centre study in Korea reported that, the proportion of Coloma de Gramenet, Barcelona, Spain patients receiving chemotherapy in the last month of life was 3 School of Medicine, Universitat Autònoma de Barcelona, 25.7% in 2000, 32.7% in 2005, and continued to increase to Barcelona, Spain 44.2% in 2010 [12]. In the USA, between 1993 and 1996, 4 Research Department, Faculty of Dentistry, University the proportion of patients receiving chemotherapy within the of Cartagena, Cartagena, Colombia 2 weeks before death rose from 13.8% to 18.5%, while recent 5 Iberoamerican Cochrane Centre, Biomedical Research studies reported stagnation in the USA [13–15]. The trend Institute Sant Pau (IIB Sant Pau), CIBER Epidemiología and magnitude of end of life anticancer treatment frequency y Salud Pública (CIBERESP), Universitat Autònoma de may be explained in part by the rapidly evolving treatment Barcelona, Barcelona, Spain options in oncology, like immunotherapy and newer targeted 6 Epidy Kft, Debrecen, Hungary 13 Vol.:(0123456789) Clinical and Translational Oncology treatments, which have broadened the therapeutic landscape. over 100 patients were included. Using this arbitrary sample Recent reviews on resource utilization in end of life cancer size criterion, the probability of random error of individual patients show great diversity in settings, methods, and out- estimates arising from low sample sizes is reduced. Due to comes across publications [11, 16, 17]. the specific disease characteristics and treatment protocols These differences are more evident when defining the of children, this review excluded studies reporting results study population. While in retrospective population-based only in paediatric patients. Moreover, randomized controlled studies, which include all cancer patients in the analysis, trials were not included in this review, as the explanatory regardless of previous treatments received or stage of can- designs might lead to an increased rate of anticancer drug cer, they typically reported a lower frequency of end of life administration at end of life. cancer treatment [15, 18, 19]. Conversely, research studies To explore the methods and outcomes used by the studies that enrolled patients with advanced cancer or those who on end of life anticancer drug use, all articles published prior had undergone cancer treatment in the past reported sub- to November 30, 2020 were included in this review, which stantially higher frequencies of end of life cancer treatment was the date of the most recent search. To provide up-to-date in the same period [20, 21]. information on frequencies of end of life anticancer drug use The goal of this article is to explore the methods and in patients with any cancer types (non-specific for tumour outcomes used by the studies, and along these differences, type or location), articles published in the last 5 years (i.e. describe the current magnitude of anticancer treatment at after January 01, 2016) were included. end of life. These objectives lend themselves to a scoping review approach because they aim to identify knowledge Selection of studies gaps, clarify concepts, and scope the literature related to cancer treatment at end of life. Scoping reviews are particu- Two authors (ES and RD) screened the search results (titles, larly useful for mapping the existing literature in a specific abstracts) against the eligibility criteria. Potentially relevant field, allowing researchers to compare the methods and out- full-text articles were selected. Discrepancies across screen- comes used by various studies [22]. In this case, a scoping ers were resolved through discussion or by a third reviewer review can provide a comprehensive overview of the current (MM). The author team selected articles for review based magnitude of anticancer treatment at end of life, highlighting on their linguistic proficiency in English, Spanish, French, differences in methods and outcomes across studies. Further- German, Hungarian, Italian, Russian, and Chinese. more, this scoping review can inform decision-making and set research agendas to identify areas that require further Data extraction investigation and inform future systematic reviews or pri- mary research on this topic [23]. As per the double data extraction method, two reviewers independently obtained data from each article and resolved discrepancies by consensus. In total, 17 undergraduate Methods medical students were trained to collaborate in the second data extraction process and checked the accuracy of coded Study identification variables on all data-entry forms. The data extraction pro- cess involved the retrieval of several key variables from the Scoping review was conducted based on the methodology included publications. These variables included the study proposed by JBI PRIMSA ScR [24–26], by undertaking a period, study design, data source, country, patient charac- systematic search in Medline (via PubMed) and Embase (via teristics (number of patients, age distribution, and gender Embase) literature databases using combinations of key- distribution), cancer stage, treatment status, cancer type(s), words (namely: ‘aggressive’, ‘end of life’, ‘last days/weeks/ inclusion and exclusion criteria, treatment type (as defined months’, ‘until/near death’, ‘late/end stage’, ‘days/weeks/ by the authors), all end of life periods reported, and the fre- months of life’, ‘antineoplastic’, ‘anticancer’, ‘chemother- quency of patients receiving anticancer treatment during the apy’, ‘hormone/immune/biological’, ‘cancer/malignancy/ specified periods. By systematically extracting and analysing neoplasm/tumour and care/drug/treatment/therapy’). The these variables, we aimed to gain a comprehensive under- search strategy developed for Medline is displayed in online standing of the patterns and frequencies of anticancer treat- Appendix 1. The research protocol is available upon request. ment utilization at the end of life across different studies. Eligibility criteria Analysis and reporting Publications reporting observational primary research stud- This scoping review adheres to the reporting standards ies on end of life anticancer drug use with a sample size of outlined by the Preferred Reporting Items for Systematic 13 Clinical and Translational Oncology Reviews and Meta-Analyses extension for Scoping Reviews Results (PRISMA-ScR) criteria [27]. The authors have followed the PRISMA-ScR checklist to ensure the completeness and Studies identified for review transparency of their review methodology and reporting. The publications were clustered according to their methodo- A comprehensive search was completed in October 2018 logical characteristics in respect of study design (prospec- and updated in November 2020 resulting in a total of tive or retrospective), data source (hospital-based medical 13,476 articles. After removing duplicates, 12,789 publi- records or population based data, including registries, claims cations were screened for eligibility by titles and abstracts. data, and administrative datasets), disease status of enrolled Subsequently, 341 publications were finally included to patients (all cancer stages or advanced cancer patients), explore and describe the various methods and outcomes patient population definition (the denominator of the propor- utilized by the studies, in accordance with the objectives of tion includes either all cancer patients or previously treated this scoping review. Furthermore, a subset of these articles cancer patients), treatment initiation (start of new anticancer (n = 69), those published in 2016 or later, were selected regimen or receiving any anticancer treatment), and anti- to analyse the current magnitude of end of life antican- cancer treatment type (as defined by the individual articles, cer drug use in patients with any type of cancer (Fig. 1). including biologics, chemotherapy, hormonal/endocrine Articles meeting the eligibility criteria that did not satisfy therapy, immunotherapy, targeted therapy, and systemic anti- the aforementioned subset requirements, including those cancer treatment). As in any scoping review, no attempts centred on specific cancer types, were preserved for poten- have been made for performing data analysis. Instead, this tial inclusion in future publications. The reference list of article describes the key study features and results across the included 341 publications and its subset of 69 articles is included studies, analysed data items by quantifying text and displayed in online Appendix 2. doing frequency counts of data extraction items with narra- tive and tabular presentation of results. Fig. 1  Scoping review flowchart 13 Clinical and Translational Oncology Characteristics of primary research articles Table 1  Characteristics of articles describing end of life anticancer reporting end of life anticancer drug use drug use (any type and specific types of cancer N = 341) Proportion of articles Analysis was performed on the characteristics of primary (number of articles) research articles reporting end of life anticancer drug use Region across 341 eligible studies to explore the common methods Africa 0.3% (n = 1) and outcomes employed by these studies. The number of Asia 16.1% (n = 55) publications increased over time, ranging from one publi- Australasia 4.4% (n = 15) cation in 2003 and peaking at 49 articles in 2018, although Europe 34.3% (n = 117) this upward trend did not continue in the in the subsequent North America 43.4% (n = 148) years (Fig. 2). Given that the article search for this review South America 1.5% (n = 5) concluded in November 2020, it is important to acknowledge Article type that the inclusion of articles published in the same year is Abstract 40.3% (n = 151) incomplete. Most of the studies (43.4%, n = 148) were from Full-text article 59.7% (n = 224) North America, with the remaining studies from Europe (34.3%, n = 117), Asia (16.1%, n = 55), Australasia (4.4%, N = total number of articles n = 15), South America (1.5%, n = 5), Africa (0.3%, n = 1). About 40% of selected studies were abstract (Table 1). Around half of the studies (47.8%, n = 163) described the frequency of anticancer drug use at the end of life in patients Methodological features of selected publications with any type of cancer aggregating all types of malignan- cies. More than one specific type of cancer (multiple) was Most studies (80.9%; n = 276) retrospectively assessed reported (up to 9 types of cancer) in 7.6% (n = 26), whereas anticancer drug use at the end of life in deceased cancer a single cancer type was assessed in 44.6% (n = 152). The patients, while 19.1% (n = 65) were prospective studies, most common cancer type was lung cancer (n = 64), fol- enrolling alive patients (Table 2). Among the whole 341 lowed by breast (n = 14), pancreatic (n = 12), and ovarian studies, 89.4% (n = 305) reported on any previously initi- cancer (n = 10). Anticancer drug use at the end of life was ated anticancer treatment, 0.6% (n = 2) reported on starting assessed for 16 further cancer types, with fewer than 10 pub- a new anticancer regimen at end of life, and 10.6% (n = 36) lications for each type (Fig. 3). reported both any previous treatment and the start of a new anticancer regimen. Chemotherapy was the most frequently Frequency of anticancer therapies at the end of life reported anticancer medication (90.6%; n = 309), followed by targeted therapies (6.2%; n = 21), hormonal/endocrine In the subset of articles (N = 69) analysed to explore the therapies (2.6%; n = 9), immunotherapies (2.3%; n = 8), and extent of end of life treatment reported across all cancer biologics (1.2%; n = 4). In addition to these specific antican- types within the last 5-year period, 27.5% (n = 19) were cer treatment types, the use of any systemic anti-cancer treat- population-based studies, all of which were retrospective. ment (SACT) was assessed in 7.0% (n = 24) of publications. Among the hospital-based studies (72.5%, n = 50), 14.0% Individualizing them was impossible due to the variations in (n = 7) were prospective, while 86.0% (n = 43) applied a SACT definitions among studies. Some publications evalu- retrospective design. With the exception of one population- ated all kinds of anticancer drugs as SACT, others focused based study, all others enrolled over 2,000 patients, with solely on chemotherapies and targeted therapies (Table 2). sample sizes ranging from 835 to 516,244 patients. Among Fig. 2  Number of articles by publication date (any type and specific types of cancer N = 341) 13 Clinical and Translational Oncology Table 2  Methodological Articles describing end of life features of included publications anticancer treatment patterns (any type and specific types of cancer N = 341) Study design Retrospective (deceased patients) 80.9% (n = 276) Prospective (all cancer patients) 19.1% (n = 65) Treatment during end of life perioda Any previously initiated anticancer treatment 89.4% (n = 305) Starting new anticancer regimen 0.6% (n = 2) Any previously initiated anticancer treatment and starting new anticancer 10.6% (n = 36) regimen Treatment typea Systemic anti-cancer treatment (all) 7.0% (n = 24) Biologics 1.2% (n = 4) Chemotherapy 90.6% (n = 309) Hormonal/endocrine therapy 2.6% (n = 9) Immunotherapy 2.3% (n = 8) Targeted therapy 6.2% (n = 21) n = number of articles; N = total number of articles a Overlap between categories is possible Fig. 3  The cancer-type specific distribution of articles describ- ing end of life anticancer treat- ment patterns (any type and spe- cific types of cancer N = 341) the hospital-based studies, the majority (54%, n = 27) more than half of the hospital-based studies (52.0%, n = 26) included less than 500 patients. The majority of population- enrolled patients who had received treatment in the past based studies (89.5%, n = 17) analysed the end of life treat- (Table 3). ment of all cancer patients, while in hospital-based studies, End of life periods analysed across the studies ranged 66.0% (n = 33) included all cancer patients, and 34% focused from 3 days to 6 months. The most commonly applied end specifically on patients with advanced-stage cancer. Around of life periods were the last 2 weeks of life (66.7%, n = 46), a quarter of the population-based studies (26.3%, n = 5) the last month of life (63.8%, n = 44), and the last 3 months focused on previously treated patients when calculating the of life (21.7%, n = 15). Multiple periods were reported in occurrence of end of life anticancer treatment. In contrast, 42.0% (n = 29) of the studies, and 11.6% (n = 8) applied 13 Clinical and Translational Oncology Table 3  Methodological features of publications describing end of (n = 9) of studies, and all of them reported at least one life treatment (patients with any type of cancer, published after Janu- further end of life period. ary 01, 2016; N = 69) In the hospital-based studies (n = 50), the frequencies of Population- Hospital-based reporting the last month of life and the last 2 weeks of life based studies studies (n = 50) were similarly high, with proportions of 66.0 and 64.0%, (N = 19) respectively. However, in population-based studies, the last Study design 2 weeks of life was more frequently reported (73.7%) com- Prospective 0% (n = 0) 14.0% (n = 7) pared to the last month of life (57.9%). Additionally, the Retrospective 100% (n = 19) 86.0% (n = 43) other end of life periods were investigated more frequently in Study sample (patients) population-based studies compared to hospital-based stud- > 2000 94.7% (n = 18) 8.0% (n = 4) ies, as shown in Fig. 4. 500–2000 5.3% (n = 1) 38.0% (n = 19) In the 46 studies assessing end of life treatment in the last 100–500 0% (n = 0) 54.0% (n = 27) 2 weeks of life, the frequency of anticancer drug use ranged Disease status between 0.2 and 29%. In the final month of life, the reported All cancer stages 89.5% (n = 17) 66.0% (n = 33) range of frequencies across publications was 1 to 56%. The Advanced stages 10.5% (n = 2) 34.0% (n = 17) 3-month end of life period was used in 15 articles, show- Treatment characteristics ing even greater variability in treatment rates, the lowest Treated and non-treated patients 73.7% (n = 14) 48.0% (n = 24) estimates reported 3% while the highest was 98%. The final Treated patients 26.3% (n = 5) 52.0% (n = 26) 2 months of life were described in 7 studies, with frequency ranging between 2 and 30%, while the last 6 months were n = number of cases; N = total number of articles reported in 6 studies (range 16–79%). The sixth most com- monly described period was the final week of life (n = 3), 4 or more different periods to determine the prevalence when between 4 and 7% of patients received anticancer of end of life anticancer drug use. In publications report- treatment. It was uncommon to report end of life anticancer ing one end of life period, the last 2 weeks of life was drug use in the last 6 days or less, in the last 3 weeks, or in used most often (52.5%, n = 21). Starting a new anticancer the last 4 or 5 months. Frequencies of end of life treatments regimen in the final months of life was assessed by 13.1% with at least two published results are shown in Table 4. The frequency of initiating a new anticancer regimen during the 1 month - starng new regimen Paents under treatment 6; 12.0% 3; 15.8% EOL period 6 months 3; 6.0% 3; 15.8% Hospital-based studies, n=50 3 months Populaon-based studies, n=19 10; 20.0% 5; 26.3% 2 months 4; 8.0% 3; 15.8% 1 month 33; 66.0% 11; 57.9% 2 weeks 32; 64.0% 14; 73.7% 1 week 2; 4.0% 2; 10.5% Time before death Frequency Death Fig. 4  End of life treatment periods analysed and their frequencies in the publications; only categories with more than one publication are pre- sented (patients with any type of cancer, published after January 01, 2016; N = 69) 13 Clinical and Translational Oncology Table 4  Reported frequency of anticancer drug use at the end of life (patients with any type of cancer, published after January 01, 2016; N = 69) End of life period 1 week 2 weeks 1 month 2 months 3 months 6 months Total 4–7% (n = 4) 0–29% (n = 46) 1–56% (n = 44) 2–30% (n = 7) 3–98% (n = 15) 16–79% (n = 6) Publication Abstract (n = 21) 7% (n = 1) 1–26% (n = 14) 5–56% (n = 15) 28% (n = 1) 19–98% (n = 5) 64% (n = 1) Full text (n = 48) 4–7% (n = 3) 0–29% (n = 32) 1–45% (n = 29) 2–30% (n = 6) 3–75% (n = 10) 16–79% (n = 5) Data source and design Hospital-based (n = 50), including: 7% (n = 2) 0–29% (n = 32) 2–56% (n = 33) 3–30% (n = 4) 5–98% (n = 10) 52–79% (n = 3) Prospective (n = 7) – 1–5% (n = 4) 5–28% (n = 6) 3–30% (n = 3) 5–36% (n = 3) – Retrospective (n = 43) 7% (n = 2) 0–29% (n = 28) 2–56% (n = 27) 25% (n = 1) 19–98% (n = 7) 52–79% (n = 3) Population-based (n = 19) 4–7% (n = 2) 1–24% (n = 14) 1–31% (n = 11) 2–28% (n = 3) 3–39% (n = 5) 16–46% (n = 3) Study sample (patients) > 2000 (n = 22) 4–7% (n = 2) 1–24% (n = 17) 1–31% (n = 14) 2–28% (n = 4) 3–53% (n = 6) 16–79% (n = 4) 500–2000 (n = 20) 7% (n = 1) 0–29% (n = 11) 2–45% (n = 12) 3–30% (n = 2) 5–67% (n = 4) – 100–500 (n = 27) 7% (n = 1) 1–27% (n = 18) 5–56% (n = 18) 11% (n = 1) 13–98% (n = 5) 52–64% (n = 2) Disease status All cancer stages (n = 50) 4–7% (n = 2) 0–29% (n = 34) 1–56% (n = 32) 2–28% (n = 5) 3–98% (n = 11) 16–79% (n = 4) Advanced stages (n = 19) 7% (n = 2) 1–24% (n = 12) 2–42% (n = 12) 3–30% (n = 2) 5–58% (n = 4) 16–52% (n = 2) Treatment characteristics Treated and non-treated patients (n = 38) 4–7% (n = 3) 0–29% (n = 26) 1–56% (n = 22) 2–28% (n = 3) 3–98% (n = 8) 46% (n = 1) Treated patients (n = 31) 7% (n = 1) 1–22% (n = 20) 5–42% (n = 22) 3–30% (n = 4) 13–75% (n = 7) 16–79% (n = 5) Treatment type SACT (n = 18) 7% (n = 1) 2–27% (n = 8) 5–35% (n = 13) 18% (n = 1) 18–58% (n = 4) – Biologics (n = 1) – 1% (n = 1) 1% (n = 1) 2% (n = 1) 3% (n = 1) – Chemotherapy (n = 54) 4–7% (n = 3) 0–29% (n = 40) 5–56% (n = 32) 10–30% (n = 6) 13–98% (n = 12) 16–79% (n = 6) Hormonal/endocrine therapy (n = 2) – 1% (n = 1) 5% (n = 1) 3% (n = 1) 5% (n = 1) – Immunotherapy (n = 3) – 2–3% (n = 2) 7–28% (n = 2) – 20% (n = 1) – Targeted therapy (n = 4) – 1–5% (n = 4) 2–5% (n = 3) – 19% (n = 1) – Region Africa (n = 1) – – 45% (n = 1) – – – Asia (n = 11) 7% (n = 1) 2–24% (n = 9) 5–42% (n = 7) 25% (n = 1) 75% (n = 1) 16% (n = 1) Austral-Pacific (n = 6) – 2–4% (n = 2) 5–31% (n = 6) – – – Europe (n = 27) 4–7% (n = 3) 2–27% (n = 18) 1–45% (n = 20) 2–30% (n = 5) 3–67% (n = 12) 46–79% (n = 2) North America (n = 20) – 1–26% (n = 14) 7–56% (n = 8) 13% (n = 1) 18–98% (n = 2) 18–64% (n = 3) South America (n = 4) – 0–29% (n = 3) 2–13% (n = 2) – – – n=Number of articles; N = total number of articles; SACT = systemic anti−cancer treatment last month before death was examined in a total of 7 stud- study sample sizes report lower frequencies of end of life ies, with reported rates ranging from 2 to 21%. One study drug use. This trend is particularly consistent in studies reported a 10% frequency of initiating a new regimen within with sample sizes over 2000 patients, where lower frequen- the last 2 weeks before death, while another study reported cies are observed across all end of life periods compared to a frequency of 9% within the last 2 months before death. studies with sample sizes below 500 patients. Studies which Stratified results of different end of life treatment periods investigated end of life drug use in advanced cancer patients showed little variation across study settings. Population- found lower frequencies in almost every periods compared based studies have lower range of end of life drug use fre- to studies which enrolled all cancer stages patients. End of quencies compared to hospital-based studies, for all periods. life cancer treatment patterns vary depending on the disease Prospective studies within the hospital-based category tend stage, with lower frequencies observed in advanced cancer to have narrower ranges for most end of life periods com- patients across almost every end of life period. Studies that pared to retrospective studies, suggesting that prospective focus solely on previously treated patients have reported designs may is associated with more focused and stand- lower rates of drug use, while studies that specify previ- ardized methodology approaches. Publications with larger ously treated and non-treated patients as the denominator 13 Clinical and Translational Oncology report higher rates in most end of life periods. Targeted ther- it aimed to explore and describe the characteristics of these apies, immunotherapies, hormonal therapies, and biologi- primary research articles, leading to the identification of key cal treatments were used in a lower proportion of patients features in 341 eligible publications, including the timing across all end of life periods, compared to chemotherapies of research, disease status, definition of treatment schedule, or SACTs (Table 4). The analysis of end of life treatment treatment type, and treatment characteristics. Secondly, to periods across different regions revealed notable geographi- achieve a comprehensive understanding of the frequency of cal differences in end of life anticancer treatment frequen- end of life anticancer drug use, we restricted our analysis to cies. Europe accounted for the largest number of estimates 69 publications concerning patients with any type of cancer regarding end of life anticancer drug use, encompassing a published within the last 5 years. This approach facilitated range of frequencies within different periods that align with detailed analyses and yielded insights into the current extent those observed in other regions. Following closely, North of end of life anticancer drug use. America emerged as the second most represented region, The broader set of 341 articles enabled a comprehensive demonstrating comparable frequencies across various end depiction of the methodologies and outcomes employed in of life periods. Similarly, Asia exhibited a notable volume these primary research studies. The number of publications of publications, presenting frequencies of end of life anti- showed that this topic has attracted more attention in recent cancer drug use that were consistent with those observed in decades, as from 2015 there was a further increase in the other regions. Within the Austral-Pacific region, data were number of articles, with a peak in 2018. The geographical available for the last 2 weeks and last month of life, showing distribution of identified articles indicates that anticancer lower frequencies in comparison to the mentioned regions. drug use at end of life is mostly reported from developed Likewise, South America reported a lower proportion of countries [35]. Probably in relation to the country’s eco- patients receiving anticancer drug in the final month of life, nomic status, cancer patients in developing regions are less while the frequencies in the last 2 weeks were comparable exposed to potential overtreatment and more frequently face to those observed in other regions. A single publication from undertreatment due to difficulties in accessing well proven Africa reported a high frequency of end of life anticancer standard therapies, coupled with a lower capacity for con- drug use in the final week of life (Table 4). ducting health research. From the other hand, resource con- straints may also limit the quantity of research conducted in low and middle income countries, moreover, it is possible Discussion that there are other factors contributing to the disparities in the number of publications. These factors could include Main findings of the study differences in research priorities, healthcare infrastructure, access to specialized cancer centres, and cultural attitudes Recent decades have seen an increasing scientific interest in towards end of life care [35]. the use of anticancer therapies at end of life. This trend is One out of seven was a prospective study. Although this presumably fuelled by the continuously growing scientific design may provide further detailed insights into the evolu- knowledge on diverse cancer types and the expanding range tion of end of life anticancer drug use, in our review, the pro- of therapeutic options available, which has a large impact spective studies had smaller sample sizes than the retrospec- on the overall treatment journey [28–32]. The benefits of tive studies, which increases the likelihood of random error. end of life cancer therapies are debated, with contradictory Conversely, retrospective studies, which accounted for the findings on their effect on survival and quality of life [1, 3, vast majority of the studies identified, can be more affected 4, 8]. To address concerns regarding cancer therapies at the by misclassification bias. The identified literature is domi- end of life, it is imperative to accurately quantify the extent nated by hospital-based studies, which had smaller sample of the phenomenon. However, this task presents consider- sizes compared to the other studies and which included able challenges due to the inherent heterogeneity in scientific every prospective study. approaches employed and the subsequent variability in the Furthermore, prospective and retrospective studies have obtained results. The multidimensional complexity of this methodological differences related to the timing of the issue includes objective and subjective factors that interact research. This impacts how the denominator of the fre- over time, contributing to the elusive nature of the end of quency is determined and, as a result, makes direct compari- life concept [33, 34]. Thus, analysing the methodological sons between the two study types challenging. In prospective characteristics of relevant research studies is a prerequisite studies, the denominator of the frequency ratio includes the to describing and understanding the current trends of cancer entire patient population, including those still alive at the therapies at the end of life. time of measurement. On the other hand, retrospective stud- This scoping review on primary research studies reporting ies employ a different methodology where treatment fre- end of life anticancer drug use had a dual purpose. Firstly, quency is measured among patients who have died. In this 13 Clinical and Translational Oncology case, the denominator is restricted to the deceased patient [16, 17]. In the systematic review conducted by Langton population. Understanding and recognizing these methodo- et al. on end of life resource utilization and costs in cancer logical disparities is crucial when interpreting and com- care, it was concluded that there are several knowledge gaps paring findings from prospective and retrospective studies in this field that need to be addressed through diverse study investigating anticancer drug use at end of life. designs and data sources. For instance, in addition to retro- Chemotherapy was the most frequently assessed treat- spective decedent designs, studies that include patients who ment type at end of life, since over 90% of studies described have survived or benefited from aggressive treatments can its frequency while other anti-cancer treatments were infre- provide a more comprehensive understanding of all patients quently reported, targeted therapy being the second most living with advanced disease [17]. Our findings present an reported (7% of articles). About half of the articles described overview of studies on end of life cancer drug use across end of life treatment by cancer type: those with high preva- different study designs and data sources, including prospec- lence, such as lung or breast cancer, or with poor prognosis, tive studies, thereby enhancing our knowledge by describing such as pancreatic cancer, were the most frequently assessed. the treatment frequencies observed along these dimensions. The subset of 69 articles on the frequency of end of life According to the review conducted by Adedini et al., the anticancer drug use showed that the most investigated end utilization of measures related to aggressive end of life care of life periods are the last 2 weeks and the last month of and oncology quality in the United States is reported to be life. The focus on these periods in research on end of life infrequent and inconsistent. For instance, only 53% of the anticancer drug use suggests a recognition of the importance included studies assessed the use of chemotherapy in the of this period and the need to optimize care during this time last 14 days of life using validated claims-based measures. to address concerns about the potential harm, reduced qual- Furthermore, initiation of a new chemotherapy regimen in ity of life, and increased healthcare costs associated with the last month of life was reported in only 6% of the studies such interventions. This observation enriches the mounting reviewed [16]. Our own findings also confirmed the infre- evidence about aggressive medical intervention at the very quent use of measures for aggressive end of life care, with end of life period, which has been recognized as inappropri- 66.7% of studies reporting the use of anticancer drugs in last ate for terminally ill individuals [36–40]. A less conserva- 2 weeks of life and 13.1% reporting the initiation of a new tive indicator of overtreatment—starting a new anticancer chemotherapy regimen in the last month of life. regimen during the last month before death—was rarely reported, although this would allow differentiation between What this study adds treatments that were started some time earlier from those that were actively initiated later on. This scoping review presents a comprehensive depiction of The overall frequency of end of life anticancer drug use research methodologies and outcomes related to end of life showed a wide range for all end of life periods, with the anticancer drug use, yielding insights into current treatment lowest values being close to zero while the highest were frequencies across various end of life periods and revealing 29 and 56% for the last 2 weeks and the last month of life, the impact of methodological features on observed variance. respectively. We observed differences of varying degrees Interpretation of the described high variability of treatments in the range of frequencies after stratifying for data source, in the end of life period is challenging since there is a lack design, size of study population, disease status, treatment of universal quality indicators of end of life cancer man- characteristics, treatment type, and region. Hospital-based agement. Studies of these indicators reveal large variations prospective and population-based studies, those with larger which can be partially explained by differences in healthcare sample sizes, that examined previously treated patients and systems and public health policies at the national level, and focused on advanced cancer cases, as well as studies involv- by heterogeneity in measurement methods and data sources ing non-conventional chemotherapy drugs, consistently [20, 41, 42]. In some countries such as USA and Australia, reported lower frequencies of anticancer drug use across doctors are more prone to prescribe anticancer therapies, various end of life periods. Our descriptive analysis did not whereas in others such as Canada, the national healthcare encompass a comprehensive multi-dimensional assessment system no longer reimburses the cost beyond a certain num- of individual factors or an evaluation of their interplay. ber of chemotherapy lines [43]. However, our findings sug- Additional methodological factors may also contribute to gest that the frequency of end of life anticancer drug use is treatment frequency, including specific cancer types exam- not solely governed by geographic factors. Further patient- ined and other considerations in defining the study popu- level factors have also been described as confounders in the lation. However, our findings are consistent with existing patterns of end of life cancer care utilization, like demo- systematic reviews on aggressive end of life care which graphic characteristics of patients [44–47], cancer stage also demonstrated high variability in the use of indicators [48–50], cancer type [49, 50], survival time [48, 51] and of aggressive end of life care and quality of oncological care comorbidities [48, 51] beyond the geographical location [41, 13 Clinical and Translational Oncology 51]. Moreover, the variability might reflect differences in Future large, multicentre studies would be the most rec- patient or family preferences, as well as potential inappropri- ommended and efficient design to establish the time pat- ate decisions made by treating clinicians [52, 53]. The inter- terns of end of life anticancer drug use, by assessing the play of these factors is complex due to overlapping charac- starting date of treatments and analysing data at different teristics, highlighting the evidence gap that remains to better time intervals. These future studies on end of life antican- explain the variation in end of life cancer care provision. cer treatment frequencies should be particularly informative regarding whether treatment is given to patients as part of standard of care or as part of an experimental study, and Strengths and weaknesses/limitations of the study ideally should collect information about the number of pre- vious treatments and clinical responses, patients’ functional This scoping review has some potential limitations. First, the status, their degree of awareness about prognostic and poten- most recent articles are underrepresented because screening tial side-effects, and eventual palliative care. Moreover, in ended in November 2020. However, the COVID-19 pan- future studies on end of life anticancer drug use, standard- demic has resulted in disruptions to cancer care, including ized methodology and study setting are warranted to achieve end of life treatments, as healthcare systems worldwide benchmarkable end of life results. struggle to balance the needs of cancer patients with the demands of addressing the pandemic [54, 55]. Therefore, we think that the publications for this period do not nec- essarily fit into the process of changes in end of life care. Conclusions Second, in spite of the high-sensitivity search strategy, key papers may have been omitted: certain stages of reviews Our scoping review provides an exhaustive description of imply a degree of subjectivity, such as selection of stud- the main characteristics of primary studies that aimed to ies, and narrative synthesis. However, thanks to the high analyse the treatments administered during the end of life degree of concordance between the different reviewers dur- period. Our results show that the proportion of patients ing the article screening process, we are confident that the receiving cancer-directed treatment at end of life varies number of potentially missed articles is low. Finally, since widely and was highly prevalent in many publications. our scoping review aimed to assess the frequency of end of However, the large methodological variability across stud- life anticancer drug use across comparable publications, we ies poses many challenges in assessing and comparing the selected studies that were homogeneous in terms of pub- extent of overtreatment at the end of life and the importance lication dates and cancer types, without considering other of its respective determinants. The enormous clinical and potentially relevant methodological factors including patient social consequences of the excessive use of aggressive treat- characteristics, therapy modalities, and disease stages. While ments in cancer patients with a very poor prognosis require the inclusion of these additional factors may have improved standardized research methods and sound indicators that can the homogeneity of the research, it would have resulted in a be applied widely. significant reduction in the number of pertinent publications Supplementary Information The online version contains supplemen- and would not have been consistent with the scoping nature tary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 12094-0​ 23-0​ 3234-1. of the review. Despite these potential limitations, our evidence scop- Acknowledgements Endre Szigethy is a doctoral candidate for the ing has several strengths. To our knowledge, this is the first Ph.D. in Methodology of Biomedical Research and Public Health (Department of Paediatrics, Obstetrics, Gynaecology, and Preventive evidence scoping review that comprehensively describes Medicine), Universidad Autònoma de Barcelona, Barcelona, Spain. the methods applied in primary research studies reporting The authors acknowledge the contribution of the medical students of end of life anticancer drug use. A high number of relevant Medicina Basada en l’Evidència Universitat Autònoma de Barcelona publications were identified thanks to the extensive and in extracting the data presented in this article. structured literature search and constitute a useful dataset to Author contributions CRediT author statement: Conceptualization: facilitate further, more specific studies. The research was not ES, GU, XB; Methodology: ES, IS, GU, XB; Validation: ES, RD, MS, restricted to full-text publications, but to ensure exhaustivity MM; Formal analysis: ES; Investigation: ES; Data curation: ES, RD, we also screened conference abstracts, letters, and editorials. MS, MM; Writing—Original draft preparation: ES; Writing—Review and Editing: GU, XB; Visualization: ES; Software: IS; Project admin- In addition to English, we reviewed publications in Spanish, istration: ES, GU, XB; Supervision: GU, XB. French, German, Hungarian, Italian, Russian, and Chinese languages reporting primary quantitative data. This scop- Funding Open Access Funding provided by Universitat Autonoma de ing review included studies with a minimum of 100 adult Barcelona. 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