How to manage symptoms in pediatric cancer patients enrolled in clinical trials? A review of principal patient-reported outcome screening tools

Introduction

Although childhood cancers are considered rare, the latest epidemiological data indicate an increase in the frequency of childhood tumors by 2% per year (1). In Italy, the incidence of tumor is 164 cases per million/year in the 0–14 age group and 269 cases per million/year in the 15–19 age group (2).

To date, despite the increase in frequency, more than 80% of children with cancer survive for at least 5 years after diagnosis, the majority of which can therefore be considered cured (3). For children and adolescents, both the cancer and the treatment generate early and long-term symptoms and adverse events (4). Treatments often put patients at risk of developing toxicity and side effects, reasons why attention must be paid to their physical and psychological state during cancer treatment. For example, most of them suffer from symptoms that are not always easily ascertained such as treatment-related fatigue, pain, nausea, cough, lack of appetite, and psychological deterioration (5). Very often children underreport their symptom severity to avoid complaining or “bothering” the physician with a symptom perceived as inherent in the treatment, or in an effort to protect their family from worries (6). Children appear very fearful and frightened during treatment and for this reason they often do not express what they feel to their parents or to the medical and nursing staff. It can happen that the voice and the needs of children are mediated by those of the parent, solicited by the doctor’s perception or ignored. In fact, some research shows that reports from doctors, nurse, or parents may not exactly reflect opinions from the child’s perspective (7).

This risk is to create barriers that do not allow children to be given a voice and these barriers can, in part, be surmounted by the use of patient-reported outcomes (PROs) that allow patients and their caregivers to feel more in control in managing their health and support clinicians in improving outcomes of care (8,9).

In adult oncology, the practice of tracking symptoms and toxicities using PROs has increased and correlates with increased survival (8). A PRO is a direct report of a patient’s condition, not interpreted or modified from a clinician. PROs are now considered the gold standard for the assessment of subjective symptoms, both in clinical practice and clinical trials so that in recent years the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have underlined the importance of PROs, also in the process of producing the evidence that leads to the approval of a treatment for use in clinical practice (10), whereas symptom monitoring using PROs is not common in pediatric oncology (11).

Only in the last couple of years has attention also been paid to the patient’s perception in pediatrics and listening to the voice of children and to making them participate in the treatment.

There is evidence that good symptom management decreases treatment-related complications and increases quality of life (4). Some study groups are committed to creating ad hoc tools for the child that are easy to understand and provide feedback to the clinicians to improve care (12,13). Greater attention must be paid to the group of patients who, due to the complexity of the disease, are enrolled in clinical trials.

Over the past 40 years pediatric oncology in Europe has made considerable progresses in increasing patient survival rates up from 10% to 80%. This was only achievable through close collaboration in multinational clinical trials (14). To date the number of children enrolled in experimental studies and clinical trials is increasing: each year more than 60% are enrolled in clinical trials (4).

Today, drug development in pediatric oncology focuses on improving survival for those patients with largely incurable tumors and attempting to use novel agents as an alternative to standard of care, thus improving the quality of survivorship (15). Patients enrolled in clinical trials are therefore often exposed to severe and demanding treatments from a physical and psychological point of view and for this reason it is desirable to offer them easy ways to express their feelings about the therapy. It is necessary to propose easily understandable detection tools that investigate not only the presence but also the frequency and severity of symptoms, in particular those not directly observable.

In this review we want to investigate the PROs used in pediatric oncology to measure self-reported symptoms in children and adolescents undergoing cancer treatment. The outcomes of interest for this narrative review include the PROs most used by clinicians and researchers and the PROs usually proposed in pediatric oncology clinical trials.

Methods

Results

Discussion

Our narrative review highlighted the most used PROs in pediatric oncology setting, by identifying 29 self-report instruments. The tools identified are aimed at giving voice to both the psychological and physical implications experienced by children and adolescents during cancer treatment.

Most of the tools are used for both aspects: Behavioral, Affective and Somatic Experiences Scale (BASES); Cancer Need Questionnaire Young People (CNQ-YP); Edmonton Symptoms Assessment System (ESAS); Functional Assessment of Cancer Therapy-General (FACT-G); Global Impression of Change (GIC); KLIK Profile; Memorial Symptom Assessment Scale (MSAS); Miami Pediatric Quality of Life Questionnaire (MPQOLQ); Play-Performance Scale (PPS); Quality of Life in Childhood Oncology (QLIC-ON); Pediatric Quality of Life Inventory (PEDSQL); Pediatric Quality of Life (PED QOL); Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE); Patient-Reported Outcomes Measurement Information System (PROMIS); Quality of Life for Children with Cancer (QOLCC); Symptom Distress Scale (SDS); Symptom Screening in Pediatrics (SSPedi); Visual Analog Scale (VAS).

Only six tools assess exclusively physical symptoms: Adolescent Pediatric Pain Tool (APPT); European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QOL-C30); Oral Mucositis Daily (OMDQ); Pediatric Nausea Assessment Tool (PeNAT); Royal Marsden hospital Pediatric Oncology Quality of Life Questionnaire (RMH-PQLQ); Wong Baker Face Pain Rating Scale.

Five of them assess only psychological implications: Cancer and Treatment Distress (CTXD); Distress Thermometer (DT); Pediatric Quality of Life and Evaluation of Symptoms Technology (PEDIQUEST); Pediatric Fatigue Short Form measures (PROMIS); State-Trait Anxiety Inventory (STAI).

Of these 29 instruments, we have identified 17 which are used in clinical trials in pediatric oncology and which therefore investigate the symptoms of children or adolescents who are following a clinical trial treatment protocol. Of these 17, most of the tools investigate both psychological and physical aspects. This is an important feature that completed the evaluation of all the aspects involved in pediatric oncology field according to a biopsychosocial way.

Increasing attention to drug development for children with cancer by regulators and pharmaceutical companies holds the promise of accelerating the availability of new therapies especially for children with resistant or relapsing cancer, potentially improving survival and decreasing the acute and chronic toxicities of therapy (15).

As novel therapies move to the front-line setting, it will be important to develop mechanisms to evaluate the potential adverse effects of these agents.

The US FDA has encouraged the use of PROs in cancer registration trials since symptomatic adverse events in pediatric cancer registration trials have traditionally been collected using clinician-reported Common Terminology Criteria for Adverse Events (CTCAE) and have not been complemented with patients’ self-report (28).

This narrative review aids pediatric oncology researchers and nursing in choosing the correct tool to measure the prevalence and the severity of symptomatology self-reported by patients during a cancer clinical treatment or trials in order to offer a better symptom management. What is also confirmed by our study is that in order to have complete information the best approach consists in the use of tools that investigate both physical and psychological aspects or that foresee the integration of the two.

Our review investigated many different tools, and thanks to the research we were able to demonstrate over time which aspects may be the most relevant to investigate. It would be useful to be able to standardize them to obtain a single clinical trial tool in pediatric oncology. Considering clinical trials, to date, it is known that the spread of the Ped-PRO-CTCAE recently developed and validated by the National Cancer Institute in several European languages offers a novel opportunity to elevate the child’s voice in drug development to inform the incidence and impact of symptomatic side effects in pediatric oncology patients.

Nonetheless, the literature on PROs goes very fast; therefore, a limit of this study is that it could be liable to bias or oversights. Those presented are certainly the main ones to our knowledge and research. Moreover, more attention should be paid to children in the 2–6 age range that is less represented. That is probably due to the fact that the competences are less developed to give an effective report about symptoms. Futures studies should create new tools appropriated to this age range.

Future objectives concern the possibility of integrating these tools in clinical practice in pediatric oncology and perhaps making them become an integral part of clinical research protocols over time with their data recorded in the medical records.

On some of these aspects there is still no uniformity, therefore it will be necessary to continue to raise awareness about the use of PROs in the pediatric oncology community.

Conclusion

We now have the knowledge to make the child’s voice an integral and fundamental part of clinical work. The dissemination and use of these tools will therefore have surprising repercussions on the control of pain and physical symptoms of small patients as well as on physical and psychological aspects.

The administration and use of the PROs ensures optimal use of the drugs currently present in clinical trials by researcher and nurse and aims at a safer and more controlled approval of new drugs.

Acknowledgments

We are grateful to UNIONE GENITORI ITALIANI – UGI and ADISCO Sezione Regionale Piemonte to sustain our project.

Disclosures

Conflict of interest: The authors declare no conflict of interest.

Financial support: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Authors’ contribution: All authors contributed equally to this manuscript.

Data availability statement: The data presented in this study are available on request from the corresponding author.