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Dealing with treatment uncertainty in elderly AML patients
Introduction
Outside clinical trials, therapy options offered to elderly acute myeloid leukemia (AML) patients are limited.1,2 They can be summarized as intensive chemotherapy (IC), low-intensity therapy (LIT) or best supportive care (BSC) depending on patient-specific3 and AML-related4 prognos- tic factors. Although scoring systems have been proposed to rationalize the medical decision-making (MDM) between intensive and non-intensive approaches,5,6 large variations in clinical practice remain,7 which underlines the paucity of evidence supporting medical decisions. International guidelines define available intensive or low- intensity options, but in most cases they give the physi- cian the responsibility of determining which option should be recommended for a particular patient. The AZA-AML-0018 and DACO 169 phase III studies failed to demonstrate the superiority of hypomethylating agents (azacitidine and decitabine, respectively) over conventional chemotherapy for patients over 65 years of age with non-proliferative AML, which increases the uncertainty regarding the optimum strategy for any indi- vidual patient. In the AZA-AML-001 trial, only 18% of patients were allocated to AZA versus IC as compared to 82% to AZA versus low-dose aracytine (LDAC) or BSC, suggesting that physicians’ decisions were already biased toward LIT. In addition, when physician-investigators in the UK National Cancer Research Institute’s AML-14 trial10,11 were offered the possibility of an optional random- ization between intensive and non-intensive therapy, they preferred to bypass this randomization and allocate their patients directly into the intensive or non-intensive arms. Multivariate comparison of the characteristics of the patients treated intensively or non-intensively in this AML trial revealed that the physician was a strong determinant of the choice, which clearly demonstrates a physician effect in this setting. Previous studies have investigated the impact of physician’s professional characteristics on their decision-making for hematologic malignancies, par- ticularly in the setting of allogeneic stem cell transplanta- tion,12,13 but these studies mostly focused on age, specialty, and hospital facility. Much less attention has been given to an individual physician’s non-professional characteristics.
Uncertainty is a crucial, multifaceted component of the therapeutic decision for older patients with AML.14 Intensive chemotherapy offers the greatest chance of complete remission (CR) but is associated with a signifi- cant risk of early death (ED), while hypomethylating agents yield a lower chance of CR but lower risk of ED. Thus, for physicians treating an older AML patient, uncer- tainty is a pre-condition for the decision itself, which underscores the need to investigate how physicians deal with it.15,16
In behavioral economics and decision sciences, attitudes towards risk and uncertainty are crucial psychological traits that may explain medical choices and practices.17,18 They aim to describe individual decisions in situations where choices have uncertain consequences. Risk- or uncertainty-averse individuals prefer a safer option (with greater chances of a smaller gain) than risk- or uncertain- ty-seeking individuals who will choose a riskier option (with lower chances of a larger gain). The difference between risk and uncertainty is that, for an uncertain option, the probability of success (or gain) is unknown. In economics, the gold standard of rationality is the expected
utility model19 (EU) although much experimental evidence in behavioral sciences shows departures from EU.20 The Allais paradoxes21,22 are decision tasks used to classify indi- viduals as conforming to EU or not (non-EU). The most popular non-EU model is prospect theory.23 Investigating the association between practice variations in AML thera- py and physician’s behavioral characteristics (such as risk or uncertainty aversion) and types (EU vs. non–EU) may help define new determinants of these variations and to propose corrective measures to improve the quality of care.24,25 We hypothesized that individual physicians’ atti- tudes towards risk and uncertainty have an impact on their decision-making process for elderly patients with AML.
Methods
Survey design
We conducted a national cross-sectional online survey of French hematologists to evaluate the impact of demographic, occupation- al and behavioral characteristics on medical decision-making for selected clinical cases of older patients with AML presented as clinical vignettes. As compared with other tools such as chart abstraction or standardized patients, clinical vignettes have been validated as a simple case-mix adjusted method for measuring quality of care and practice variations.26 All the hematologist- oncologists practising in France who provide direct patient care for adults with AML were eligible. A first draft of the questionnaire was developed and subsequently modified after pilot testing with 20 hematologists. Overall, the survey contained 27 questions and took 10-15 minutes to complete. The questionnaire is available in Online Supplementary Appendix Section I.
Survey instrument
Physician’s demographic and occupational characteristics included age, gender, medical specialty, subspecialty, hospital facil- ity, hierarchical position, year of graduation, patient volume (num- ber of AML patients aged 60 years or older each physician treated annually), and self-evaluation of expertise in the field of AML.
Four hypothetical AML patients aged 60 years or older were selected as representative of clinical practice and were summa- rized by 3 local specialists (PB, SB and CR) as Vignettes #1 to #4 (Table 1). Each of these cases highlighted distinct and difficult rep- resentative situations regarding their age, comorbidity, family environment or AML biology. Vignettes #5 and #6 were similar to Vignette #4 but included a unique variation related to age (increased from 63 to 73-years old in Vignette #5) or white blood cell (WBC) count (increased from 2.5 to 40 x109/L in Vignette #6). For each of these 6 vignettes, the close-ended treatment options were: 1) intensive chemotherapy; 2) low-intensity therapy; or 3) best supportive care.
To measure physicians’ attitudes towards risk and uncertainty, we used four different elicitation methods (Figure 1) that have been validated in representative national surveys.27 The first two measures are certainty equivalent elicitation and the third one consisted of two binary lottery choices. These tasks involve risky choices with financial consequences. The fourth method is a Likert scale that measures willingness to take risks in four different domains (Online Supplementary Appendix Section II).
Survey implementation
The Ethics committee of the French Society of Hematology approved the study and provided an incentive email accompanying the online survey invitation. Physicians identified from the French
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