The discontinuation of antitumor treatment and the advance directives in cancer patients

Advance directives (AD) are an essential part of the Advance Care Plan (ACP), which aims to improve patient care, quality of life, and reduce health costs.^[ 1 ^] The formulation of an AD involves a behavioral change and a better understanding of the context of a terminal disease, taking into account the values, beliefs and objectives of the patient.^[ 2 ^] The prevalence of advance directives in the USA ranged from 5-37% but this number can reach 70% in samples affected by terminal conditions.^[ 3 4 5 6 ^]

The benefits of advance directives include reduction of in-hospital mortality rates, higher levels of patient satisfaction, the accomplishment of patient's wills, and reduction of depression and anxiety in end-oflife, for patients and their relatives.^[ 7 8 9 10 11 12 ^] The relevance of AD grows exponentially as we look at the current reality of Oncology and the “chronification” of disease. The process of “chronification” of disease put the ADs into a risk of being undervalued or postponed. That leads us to a potentially negative impact with unwanted costs in a collapsing global health system.^[ 13 14 15 16 ^]

Every oncologist treating incurable cancer patients in daily practice recognizes the impact of the discontinuation of anticancer treatment and the beginning of the called Best Supportive Care (BSC) modality of treatment. Despite this, there is a lack of data regarding the association of discontinuation of antitumor treatment with advance directives elaboration and implementation. The primary objective of this study is to evaluate if the moment of discontinuation of antitumor treatment could influence the rates of advance directives.

A total of 390 electronic medical records were accessed and 321 subjects confirmed all eligibility criteria and were included in the analysis. The demographic characteristics of the groups with and without advance directives were balanced and summarized inTable 1 . The prevalence of advance directives was 22.7% and 74% of subjects received at least one cycle of antitumor treatment, a high rate based on literature evidence.^[ 23 ^]

The group with AD correlated more with the registry of treatment discontinuation compared versus the no AD group (87.7% vs 77.6%) and temporal correlation analysis found that the treatment discontinuation decision occurs on the same day or before the first AD manifestation in 82.3% of cases.

Looking at the moment of treatment discontinuation, the place at this moment seems to correlate in a different way between the groups with and without ADs, as demonstrated inFigure 1 . The group with advance directives was more correlated with the outpatient scenario than the group without advance directives (82.5% vs 64.4%, respectively; RR 1.88; 95%CI 1.019-3.496; p =0.043) by multivariate regression. The same analysis did not show a significant association between ECOG performance status (0-3 vs 4) and the two groups in the moment of BSC beginning ( p =0.137).

An analysis, independent of the advance directive status, was performed to access the correlation between performance status and place where BSC was implemented. A statistically significant correlation was found between better performance status (PS ECOG 0-3) and the outpatient scenario in comparison with hospitalized patients (RR 1.835; 95% CI 1.387-2.429; p <0.0001), as demonstrated inFigure 2.

There was no statistical difference in outcomes between the groups with and without an AD. The outcomes included the limitation of therapeutic resources, place of death, receipt of blood components, ICU admissions, invasive palliative procedures (drainage of cavities, biliary tract and derivation of intestinal transit in the majority), the specialty at last assistance, cause of death, orotracheal intubation, mechanical ventilation, artificial parenteral hydration and enteral nutrition, and use of broad-spectrum antibiotics did not differ between groups with and without AD (Table 2). The time interval between the palliative diagnosis and the start of BSC, limitation of therapeutic resources, and death also did not differ between the two groups. The median interval from palliative diagnosis to death differed by 3 days between the groups with and without advance directives. The most cited first living will was the “desire to die at home”, representing almost 30% of the registries. Among those patients that reported this desire, 13.6% died at home, compared with 64% of inhospital deaths.

The positive correlation between the group with advance directives and the outpatient scenario in the moment of discontinuation of anticancer treatment could be explained by a greater sense of security, confidence and stronger relation with the assistant professional.^[ 24 25 ^] These factors facilitate the transition to a BSC approach and also improve the chance of discussions about the advance care plan and advance directives providing patients with more autonomy. The emergency, wards and ICUs environment interfere negatively in the compliance and elaboration of an advance care plan and advance directives. A good and early advance directive can reduce visits to the emergency department (as illustrated by the 14.8% vs 18.5% deaths in the emergency), and could also reduce stress and possible iatrogenic measures as stated by the literature.^[ 26 27 28 ^]

Despite no correlation founded between the performance status and ADs documentation, in daily practice, we observe that the more debilitated patients are less capable to discuss advance care plan and manifest their advance directives. The prognostic impact that poor performance status carries may reinforce mercy feelings by oncologists and/or family members.^[ 29 ^] A deleterious practice called collusion may occur in this scenario and it refers to the attitude of put aside the patient's autonomy and restricts the decision process to relatives and medical team, hiding the truth and facts from the major interested person.^[ 30 ^]

A fact that suggests the presence of collusion in this study population is that despite low rates of ADs, low rates of life-sustaining measures were verified. We also know that patients on PS ECOG 4 also have more cognitive dysfunctions and weaknesses that may compromise their interest and ability to formulate advance directives in time to honor their living wills.^[ 31 ^] The independent analysis correlating patients in PS ECOG £ 3 with the outpatient scenario in comparison with PS ECOG 4 (RR 1.835; p <0.0001) corroborates this argument.

The 22.7% prevalence of advance directives found in our study is below that described in North America but is consistent with data from other localities.^[ 3 4 5 6 32 33 34 ^] We highlight some possible explanations as a low educational level in our sample (more than 50% without the basic educational level completed), the recent history of use of ADs in Brazil, its low dissemination in the health system, and the information bias inherent to retrospective studies.

Where the oncologic patients have died is an important topic. A large cross-national study involving people with cancer found a large variety of in-home deaths ranging from 12-57%.^[ 35 ^] In this study, 13% of patients died at home despite being the most cited first directive recorded. Of the 22 patients who registered a directive expressing the will to die at home only three (13.6%) actually did, compared to fourteen (63.3%) dying in the hospital. This data clearly indicates the difficulty in honoring this type of living will, suggesting the multifactorial influence acting on the final results. One of the multiple factors for this discrepancy is the low prevalence of outpatient hospice care the Brazilian public health system, a factor that is correlated with more deaths in the setting of choice.^[ 36 ^] Other factors may include losses of ADs in the transition between different health teams, lack of a standardized AD registry and inefficient ways to keep it easily accessible.^[ 37 38 ^]

Although the literature indicates a correlation of the advance directives with a reduction in the adoption of aggressive and life-sustaining measures in the terminal setting, in this study the presence of living wills did not statistically correlate with less life-sustaining treatments.^[ 39 ^] This could be due to underestimation of AD caused by discussion without adequate documentation, difficulty in talking with patients about therapeutic limitations leading to relative-guided decisions, and simply beliefs by family members and physicians that some life-sustaining measures could have a positive impact on the lifetime of a terminally ill patient, generating the high rates of parenteral hydration and broad-spectrum antibiotics. Finally, in accordance with literature evidence, our data show no difference in the survival curves between the groups with and without advance directives.^[ 40 41 ^]

We must consider that, like any observational study, this research is subject to observational study biases and the results serve as a hypothesis generator. Although it is not able to directly establish a causal relationship, it provides a statistically significant correlation between advance directives registration and the outpatient setting when the anticancer treatment was discontinued, something based on the theoretical rationale. This type of observational data brings the possibility to change practice improving care of palliative cancer patients by discussions and elaboration of advance directives, patients the opportunity to have their wills honored. Finally, we should always keep in mind the multifactorial pattern that influences the composition of advance directives and impaired solid base evidence in this field of research. (Figure 1).

Advanced directives in Brazil, Latin America and all around the world need to be further studied from a clinical perspective, in addition to the legal and psychological view. More prospective large-scale studies are needed to add data to the literature, including intervention studies. The present study is the first to demonstrate that the place of discontinuation of antitumor treatment affects the advance directives rates, and is the first study assessing the reality of advance directives amongst oncologic patients in Brazil.

This conclusion is important if we consider the current development of the therapeutic arsenal and the prolongation of patient survival, with a concomitant gain in quality of life and “chronification” of disease. It brings a natural tendency to postpone the discussion of the advanced care plan to a later moment after all therapeutic lines had failed. The transition to best supportive care could represent a window for discussions about end of life, for the valorization of patient's autonomy, selfdetermination, and to preserve dignity in the death and dying process. In addition, this study suggests that the outpatient scenario is the best for the elaboration of advance directives. Medical assistants should always discuss the aspects of the end of life care with their patient, preferably in the office and on the most appropriate occasions. The focus should always be on dignity and respect for the desires of the patient, from the beginning to the end.