Adolescents’ understanding of chemotherapy-related adverse events: a concept elicitation study

Abstract Objective: to document adolescents’ understanding of chemotherapy-related core adverse events from the Pediatric Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events and thus begin the validation process of this tool’s items with Brazilian adolescents. Method: this is a prospective, qualitative study of concept elicitation. The participants were 17 adolescents aged 13-18 years and undergoing chemotherapy in three hospitals in São Paulo - SP, Brazil. Cognitive interviews were conducted with questions based on chemotherapy-related adverse events. Data were analyzed for responsiveness and missingness. Results: adolescents could and were willing to provide descriptive information about their chemotherapy adverse events, including physical and emotional events. Some participants suggested alternative terms to name the adverse events and some used more complex terms, but most were satisfied with the primary terms used by the researchers. Conclusion: this study represents the first steps towards understanding how adolescent cancer patients identify, name, and describe these events by cognitive interviewing to help design future assessment instruments focused on this age group.


Method Study design
This prospective concept elicitation study used descriptive cognitive interviewing (CI) to explore adolescents' understanding of the adverse events of chemotherapy. CI is essential to develop, to refine, or to validate questionnaires or measures (14) . It can be both reparative and descriptive (14)(15) . The United States Food and Drug Administration (FDA) and the literature on measurement tools development recommend conducting qualitative interviews with specific populations to support item generation and the content validity of Patient-Reported Outcomes (PRO) instruments (16) .
Cognitive interviewing can also be conducted without a specific measurement tool or a questionnaire when it aims to understand the behavior, the interpretation, or the comprehension of a specific population or construct of interest, as intended in this study (17) . A free-form format of descriptive cognitive interviewing was adopted to explore the constructs and specific language that adolescents with cancer use to describe the adverse events of chemotherapy. Data were collected from medical records, including patients' underlying disease, information about the protocol used, and phase of treatment during data collection.

Data collection
For this study, the terms referring to adverse effects extracted from the Pediatric PRO-CTCAE ® were translated into and adapted for Brazilian Portuguese and later validated by three specialists in pediatric oncology, who assessed the efficiency of the translation of terms and their correspondence according to the following classifications: 1. adequate; 2. partially adequate; 3. inadequate. When items were classified as 2 or 3, professionals were asked to suggest the changes they deemed appropriate. To check the reliability and 1 Abdominal pain (Belly pain) 9 Fever  Questions targeted a seven-day recall period, same as prior pediatric cancer studies (21)(22)(23) . Initially the plan was to ask adolescents about four randomly selected AEs, but all participants showed readiness and interest to continue describing more events, with no signs of tiredness or apparent distraction. The mean duration of the interviews was 16 minutes.

Data analysis
After data collection, the interview was transcribed by two research assistants and validated by the main investigator. Accordingly to CI, verbal probing approaches were used to assess adolescents' interpretations of each AE. The primary analysis was qualitative according to the content of phrases and the AE descriptions provided by adolescents, as recommended by the CI method (14) . The adolescents were also interviewed regarding their attributions and understanding of the events that preceded the AEs and the following outcomes.

Physical AEs
Gastrointestinal AEs were the most detailed physical events, including described duration, precipitating factors, and characteristics. To refer to nausea, the adolescents used the original term "nausea" and "feeling sick" instead of "sickness":

Feelings and emotional AEs
The cognitive interviews included emotional changes such as sadness and unhappy feelings

Discussion
Concept elicitation by qualitative interviews promotes engagement and valuable inputs from the target population, allowing individuals to state the significance and impact of these events on their lives before researchers introduce a standardized or predetermined list of AEs (19,24) (25)(26)(27) . Moreover, the interviews allowed the researchers to analyze and to report the vocabulary that adolescents use to describe these events.
Notably, participants indicated precipitating factors to some AEs or described known classifications to considered a physical symptom despite being related to fatigue, a constitutional symptom. Adolescents may have difficulty in differentiating tiredness (fatigue) from weakness since these AEs, although different, frequently co-occur (21,27,37) .
Tiredness was the most used term to describe fatigue caused by chemotherapy treatment, corroborating other studies (19,21,27) . Fatigue is considered one of the most prevalent AEs experienced by adolescents with cancer and encompasses physical, psychological, and cognitive aspects (28) . It is a complex AE that affects the quality of life of pediatric oncology patients (12) . As the literature reports, fatigue is also associated with depressive symptoms and behavioral changes (27,37) . Participants reported that fatigue affects their routine activities, corroborating another qualitative study with adolescents undergoing chemotherapy (4) .
The first study to examine the fatigue and We observed that interviewees tended to talk about emotions when asked explicitly about feelings, not spontaneously. A study with American adolescents showed that participants responded to psychological wellness questions separate from physical wellness questions, different from adults (19) . The mood of some study participants fluctuated between sadness and anger. The prevalence of mood changes in adolescents undergoing chemotherapy varies from 30 to 70% in the literature (28) . Sadness was also associated with other AEs, such as depression and alopecia. Moreover, changes in appearance had an emotional impact on participants, as observed in the literature (4,(27)(28) . Research cites emotional instabilities as very uncomfortable AEs for adolescents, affecting their social relationships (i.e., parents and friends) (28,37) . Some drugs, such as corticosteroids, can significantly change mood and irritability (28) . Other emotional symptoms identified corroborate the literature, including anxiety and depression (19,27) . including adolescents (19,21,23) .
As for the reference period, most of the instruments aimed at adolescents use one week or a seven-day recall period (3,19,21,23) . However, researchers still have difficulty in establishing this duration due to the cooccurrence of different AEs and the individual variations and differences in therapeutic protocols (23) . Defining the recall period is essential in self-report instruments, whether focusing on adult patients, adolescents, or children (19) .
Only one participant mentioned cough, apparently due to a pulmonary infection. In the context of chemotherapy, cough can be secondary to pulmonary fibrosis, induced by some antineoplastic drugs such as Busulfan, Cyclophosphamide, Methotrexate (MTX), Mitomycin, and FOLFOX protocol drugs (Folinic Acid, 5-FU, and Oxaliplatin). Some of these drugs are more used in adolescents than in children (28) . to the design of assessment instruments focused on this population to prevent, detect, and manage these events appropriately, with no interruptions in treatment planning and improving the quality of life of these patients.