Introduction
Collectively, the physical and psychosocial well-being of individuals receiving health care is termed health-related quality of life (HRQOL). This concept differs from the broader concept of overall quality of life which may include environmental, political, or economic issues in addition to health-related concerns [
1]. The inclusion of HRQOL as an evaluable endpoint in cancer treatment and symptom management trials is important for a number of reasons. It can be used as part of an evaluation of the effectiveness of a treatment or to discriminate between two treatments with equivalent efficacy, but different toxicity profiles. This information can be used in a shared decision-making process with children and parents, because even small changes in HRQOL that occur early in a child's life may cause large cumulative effects over time in quality-of-life years lost [
2].
Prior to 2000, very few clinical trials with pediatric oncology patients evaluated HRQOL as a study endpoint [
3]. However, at the present time, many Phase III chemotherapy (CTX) trials collect data on HRQOL to supplement data on survival rates. In addition, HRQOL endpoints are being used in nearly 75% of oncology symptom management trials [
4] as a result of a mandate by the Food and Drug Administration to include patient reported outcomes (PROs) in clinical trials [
5,
6].
Most HRQOL research in pediatric oncology focuses on survivors of childhood cancer [
7]. Only a limited number of studies have identified the factors that affect HRQOL in children who are receiving active cancer treatment [
8‐
17]. Only four of these studies included patients receiving intensive CTX [
8,
10,
15,
18], and none included children who received only myelosuppressive CTX. Some information, albeit limited in quantity, is available regarding the relationships between demographic (e.g., age, gender) and clinical characteristics (e.g., treatment status, comparisons among various cancer diagnoses) and HRQOL of children who received cancer CTX. In addition, the relationships among functional status, symptom occurrence rates, and HRQOL of children with cancer were assessed in only one study [
19]. Therefore, the purposes of this study, in children who were assessed 1 week after the administration of myelosuppressive CTX were: to compare the total and subscale scores on a generic measure of HRQOL (i.e., the Pediatric Quality of Life Inventory 4.0 Generic Core Scale) to normative data from healthy children and to describe the relationships between demographic, clinical, and symptom characteristics of children with cancer and generic and disease-specific dimensions of HRQOL. It was hypothesized that the HRQOL scores of children with cancer would be lower than those of healthy children.
Patients and methods
Patients and procedures
This descriptive study used self-report questionnaires to obtain information from a convenience sample of children and adolescents with cancer (10 to 18 years of age) who were able to understand English or Spanish and give assent or consent to participate and were receiving myelosuppressive CTX. Participants were receiving CTX either as their initial therapy or for relapsed or refractory disease and had received at least one prior course of CTX. Children younger than 10 years of age were excluded because the instrument used to evaluate symptoms was validated in patients between the ages of 10 and 18 years.
Myelosuppressive CTX refers to treatment that is expected to cause a significant drop in the absolute neutrophil count to less than 500 cells/μL, with subsequent blood count recovery expected to occur within 3 to 4 weeks. Similar CTX regimens were targeted for selection among common diagnoses (e.g., doxorubicin with cisplatin for osteosarcoma and cyclophosphamide with cytarabine for acute lymphocytic leukemia). Patients were excluded if they were receiving concurrent radiation therapy. Patients were recruited from three pediatric oncology settings in the San Francisco Bay area.
Between February 2008 and February 2009, a total of 73 patients were approached to participate, and 66 provided assent or consent (response rate of 91.4%). Of the eligible patients available, approximately eight were not approached because research staff were not available at the site. The primary reason for refusal was that patients were not interested in completing questionnaires. While data were collected weekly over a 3-week period (i.e., prior to the administration of CTX, 1 week following CTX administration, and 2 weeks following CTX administration), the HRQOL data reported in this paper is from the second time point (i.e., the week following CTX administration). Patients' symptoms were expected to be the most frequent and severe at this time point. In addition, previous research found the HRQOL of pediatric oncology patients was lowest in the days immediately following CTX [
8].
The study was approved by the Human Subjects Committee at the University of California, San Francisco, and at each of the study sites. Patients' parents or guardians and patients who were 18 years of age signed a written, informed consent. Patients aged 10 to 17 (85%) gave either written or verbal assent as per each institution's guidelines.
One week after the administration of CTX, children completed the Memorial Symptom Assessment Scale for 10- to 18-year olds (MSAS 10–18) [
20]. In addition, they completed the age-appropriate versions of the Pediatric Quality of Life Inventory 4.0 Generic Core Scale (PedsQL™ 4.0 GCS) [
21,
22], the Pediatric Quality of Life Inventory 3.0 Cancer Module Scale (PedsQL™ 3.0 Cancer) [
23], the Karnofsky Performance Status (KPS) scale [
24], and a weekly data form to capture information not uniformly included in the medical record (e.g., number of hospitalizations, fever). Children were asked to respond to each question based on their experiences during the week following CTX administration. Children received support from the the research assistants to complete the study questionnaires as needed in person (if the patients were hospitalized or had clinic appointments) or via telephone. English and Spanish versions of the PedsQL™ were available. The MSAS 10–18 was translated from English to Spanish using forward and backward translation procedures. Patients’ medical records were reviewed for disease and treatment information. The children were given a $50 gift card to compensate them for their time.
Instruments
The revised version of the MSAS 10–18 assesses 31 symptoms on three dimensions. If patients reported the occurrence of a symptom over the previous week, they rated the symptom's frequency (1 (almost never) to 4 (almost always)), severity (1 (slight) to 4 (very severe)), and distress (0 (not at all) to 4 (very much)) using Likert scales. Positive responses were summed to determine the total number of symptoms experienced. Severity and distress ratings were assigned a value of zero when the symptom was not reported. The severity and distress ratings for all 31 symptoms were averaged to calculate the mean ratings for these two dimensions. The MSAS 10–18 was chosen because it is a multidimensional symptom inventory that evaluates 31 symptoms, yet can be completed in less than 15 min [
20]. The MSAS 10–18 has established validity and reliability [
20].
The PedsQL™ is a modular instrument that consists of a generic measure and disease-specific modules. The generic version of the instrument (i.e., PedsQL™ 4.0 GCS) has been used extensively to assess HRQOL in both healthy and chronically ill children with a variety of medical conditions, including cancer. It is a 23-item instrument that evaluates the following dimensions of HRQOL: physical, emotional, social, and school functioning [
21,
22]. In this study, the acute version of the instrument was used. Patients responded using the time frame of the past 7 days, using 5-point Likert scales (i.e., 0 (never a problem) to 4 (almost always a problem)). Items are reverse scored and linearly transformed to a 0 to 100 scale, with higher scores indicating a better HRQOL. A total and four subscale scores are calculated (i.e., physical functioning, emotional functioning, social functioning, school functioning).
The cancer-specific instrument used in this study was the PedsQL™ 3.0 Cancer Module Acute Version [
23], a 27-item multidimensional survey with eight subscales (i.e., pain and hurt, nausea, procedural anxiety, treatment anxiety, worry, cognitive problems, perceived physical appearance, communication). The response format and scoring procedures are similar to those for the PedsQL™ 4.0 GCS.
Each of the HRQOL instruments takes less than 5 min to complete. Both forms of the PedsQL™ have established validity and reliability [
21‐
23]. In this sample, Cronbach's alpha coefficients for the PedsQL™ generic and cancer versions were 0.89 and 0.90, respectively.
The KPS scale was used to assess patients' functional status. KPS scores range from 0 (dead) to 100 (normal function) in 10-point increments [
24]. The KPS has well-established validity and reliability in adults [
25‐
28] and has been used in pediatric studies [
19,
29‐
31].
Analytic methods
Data were analyzed using SPSS® version 15.0 (SPSS, Inc., Chicago, IL). Descriptive statistics were generated on the sample characteristics. Because HRQOL scores did not differ significantly by study site, or language, data were analyzed for the entire sample. One sample t tests were used to compare total and subscale scores on the PedsQL™ between children with cancer and normative data on healthy children. Independent samples t tests and Pearson's product-moment correlations were used to examine the relationships between demographic characteristics (i.e., age, gender, race/ethnicity), clinical characteristics (i.e., number of inpatient days, number of relapses, KPS scores), and symptom characteristics (i.e., number of symptoms, mean symptom severity, mean symptom distress) and generic and disease-specific measures of HRQOL. In order to control the type I error rate, a p value of <0.01 was considered statistically significant.
Discussion
To our knowledge, this study is the first to describe the relationships between functional status and a number of symptom characteristics and generic and disease-specific measures of HRQOL in a relatively homogeneous sample of children who underwent myelosuppressive CTX. The effect sizes for differences in pediatric oncology patients’ physical subscale scores compared to those of healthy children were greater than for the psychosocial subscales. Based on a cutoff score of 1 SD below the population norm, over 75% of children in this study met this cutoff for the physical functioning subscale score and over 25% met this cutoff for the total, emotional functioning, and school functioning scores (Table
2). In addition, for the total, physical functioning, and school functioning scores, these differences met previously established criteria for clinically meaningful decreases in HRQOL [
32]. These findings are similar to those reported for children with brain tumors during their first year after diagnosis [
17], children with brain tumors on and off treatment [
33], and for a heterogeneous sample of children receiving active treatment for cancer [
15].
An interesting finding from this study, that is consistent with previous reports, is that no between group differences were found in children's scores on the emotional [
17,
33] and social functioning [
17] subscales of the PedsQL™ generic version. Our quantitative data support the hypothesis proposed by Penn et al. [
17], that children with cancer may not understand the consequences of their malignancy; may repress symptoms of emotional distress; or may be reluctant to provide details of their emotional state [
17]. Alternatively, children with cancer may develop an astounding degree of resiliency [
34]. Additional investigations are warranted, perhaps using qualitative research methods that explore the impact of cancer and its treatment on children's emotional and social functioning.
In terms of the cancer-specific HRQOL measure, the worst scores reported were for nausea (68.9), worry (69.5), and pain and hurt (72.3). Only three studies have reported subscale scores on the PedsQL™ cancer module from children during CTX [
11,
23,
35]. Our findings are similar to most of those reported in previous studies. However, children in this study reported less nausea and procedural anxiety than Brazilian children on CTX [
35]. The supportive care interventions readily available in the United States (e.g., general anesthesia during invasive procedures, more routine use of antiemetics) may explain these differences. In addition, compared to data from Varni et al. [
23], our sample reported less procedural anxiety than children on CTX in the late 1990s. General anesthesia was not commonly used for invasive procedures at that time. Future studies need to evaluate HRQOL in relationship to various supportive care measures and how these scores change over the course of cancer treatment and into survivorship.
The lack of many gender [
36‐
38] and racial/ethnic differences [
39] in generic and disease-specific dimensions of HRQOL are consistent with previous reports of children with cancer who received CTX. To date, only four studies have identified gender differences in HRQOL. Girls reported lower HRQOL scores than boys on various subscales in three of these four studies [
15,
39,
40]. In addition, in two studies [
36,
37], white children reported better HRQOL than children from racial/ethnic minority groups. While a few studies found that older children reported a poorer HRQOL, these differences were generally in the psychosocial dimensions [
15,
37,
41‐
43], and were contradicted by other studies [
36,
39,
42]. These inconsistent findings may relate to variations in the HRQOL instruments used, comparisons between children's self-reports and proxy reports, and small sample sizes. While few differences in HRQOL were noted when demographic characteristics were compared in a large population-based study of the PedsQL™ [
32], these inconsistent findings in oncology patients warrant additional investigation.
In terms of clinical characteristics, while the number of days hospitalized and the number of relapses were not associated with any generic or disease-specific dimensions of HRQOL except nausea, children with lower KPS scores reported significantly poorer scores on almost every generic dimension of HRQOL. The strongest correlations were found with the physical and social functioning dimensions of the generic measure. Clinicians' familiarity with the KPS, its simplicity of use, and the strong correlations with HRQOL make it an ideal metric to include in additional HRQOL research.
The moderate correlations between the various symptom characteristics and the various dimensions of the generic HRQOL measure suggest that the total number of symptoms, as well as severity and distress associated with these symptoms have a negative effect on children’s HRQOL. On average, children in this study reported ten symptoms in the week following the administration of CTX. While the mean symptom severity (0.7) and distress (0.6) scores were relatively low, these scores included ratings on all 31 symptoms with zeros for symptoms that were not present. Our findings are consistent with previous reports that found that higher symptom severity and interference scores were associated with poorer HRQOL in a sample of children who were on and off therapy [
19], as well as in a study of adolescents and young adults with cancer and blood disorders [
44].
A study of the associations between symptom characteristics and HRQOL poses some conceptual challenges. First, the issue of the causal relationships between symptom number, severity, and distress and decrements in HRQOL are difficult to differentiate. Clearly, some symptoms may cause decrements in HRQOL (e.g., nausea may cause poor HRQOL). However, HRQOL may also affect symptom occurrence (e.g., insomnia or anxiety may be caused by decrements in the social functioning or school functioning dimensions of HRQOL) [
45]. In addition, many HRQOL measures, like the measure used in this study, include one or more dimensions that evaluate symptoms. Future studies that include a longitudinal evaluation of both symptom characteristics and various dimensions of HRQOL and the use of more sophisticated statistical techniques may be able to determine cause and effect relationships.
Several study limitations need to be acknowledged. The relatively small sample size and heterogeneous population limited the use of multivariate methods to predict decrements in HRQOL. Despite these limitations, this study adds to the growing body of knowledge of the factors that affect HRQOL. Future research should focus on patients who are similar with respect to diagnosis and treatment regimen, and time since diagnosis in order to eliminate potential confounding factors. Such a study, with national or international collaborations, would further delineate the factors that affect HRQOL in order to identify children who are at higher risk for decrements in HRQOL and to be better able to initiate optimal treatment regimens for these children during cancer CTX.
This research was supported by a grant from the National Institute of Nursing Research (NR010600). Dr. Baggott received support from the American Cancer Society, the Betty Irene Moore Doctoral Fellowship in Nursing, and the Oncology Nursing Foundation.