Quality of life Acute health-related quality of life in children ... - Nature

Bone Marrow Transplantation (2002) 29, 425–434  2002 Nature Publishing Group All rights reserved 0268–3369/02 $25.00 www.nature.com/bmt

Quality of life Acute health-related quality of life in children undergoing stem cell transplant: I. Descriptive outcomes S Phipps1, M Dunavant1, PA Garvie1, S Lensing2 and SN Rai2 1

Divisions of Behavioral Medicine, St Jude Childrens Research Hospital, Memphis, TN, USA; and 2Division of Biostatistics, St Jude Childrens Research Hospital, Memphis, TN, USA

Summary: There has been little empirical documentation of the acute effects of bone marrow or stem cell transplant (BMT) on children. In the present study, the responses of 153 children undergoing BMT were assessed in a prospective, longitudinal design. Children were assessed at the time of admission for transplant, then underwent weekly assessments to week ⴙ6, followed by monthly assessment to month ⴙ6. Data were obtained both by parent report and patient report (for patients age 5 and up) using the BASES scales. The major findings are: (1) children undergoing BMT enter the hospital with an already heightened level of distress (defined by high levels of somatic symptoms and mood disturbance, and low levels of activity) that increases dramatically following conditioning, reaching a peak approximately 1 week following transplant; (2) this increased distress is transient, declining rapidly back to admission levels by week ⴙ4 to week ⴙ5, followed by a further decline to presumed basal levels by months 4–6; and (3) the trajectories of distress depicted by both parent and child report are remarkably similar, each providing confirmatory support for the validity of the findings. These findings confirm a number of widely held clinical impressions that had not previously been documented empirically, and point to the need for new interventions or more intensive approaches to supportive care aimed at reducing levels of distress during the acute phase of transplant. Bone Marrow Transplantation (2002) 29, 425–434. DOI: 10.1038/sj/bmt/1703377 Keywords: bone marrow transplant; children, hospitalization; distress; mood disturbance; quality of life

Although it is generally accepted that bone marrow or stem cell transplantation (BMT) is a very demanding and stressful experience for children, the degree to which the process Correspondence: S Phipps, Division of Behavioral Medicine, St Jude Children’s Research Hospital, 332 N Lauderdale, Memphis, TN 381052794, USA Received 25 September 2001; accepted 16 November 2001

of BMT causes distress in children has not been widely studied empirically. To date, research on the psychosocial consequences of BMT has come primarily from studies of adult patients, with only a small number of studies involving pediatric samples.1,2 The adult BMT literature, while more extensive, has also been largely focused on late effects and patient quality of life post BMT, rather than the acute distress and disruptions in psychosocial functioning during the transplant procedure.1,2 Studies addressing acute issues have frequently been limited by retrospective designs, with the few prospective studies involving very small samples,3–6 particularly in pediatric populations.7,8 The available prospective studies have provided a mixed picture, with some suggesting moderate to high levels of anxiety and depression,3–5 and others indicating relatively low levels of emotional distress.6 Perhaps the most comprehensive prospective study was reported by Hjermstad et al,6 who assessed patients on multiple occasions during the first year following BMT. They found a moderate, transient increase in symptoms of anxiety and depression during the acute isolation period, which then declined and stabilized by 4 months post BMT. This pattern differs from the more commonly depicted ‘trajectory to recovery’ following transplant, in which patients have been reported to show gains in functioning for up to 2 years post BMT, before leveling off.9–11 It may be that there are two separate trajectories, one reflecting acute processes and mood disturbances specific to the transplant procedure, which recovers more quickly, and a second trajectory related to more global quality of life, which shows a longer time to recovery. The available data from children are too limited to draw any such conclusions, although a short-term prospective study by Rodrigue and colleagues7 showed results comparable to those of Hjermstad,6 with elevations in ratings of pain and anxiety at 2 weeks post BMT, which subsequently declined through week ⫹5. A retrospective study of child BMT patients suggests that children may experience milder levels of distress than those reported by adults.12 A limitation of the available longitudinal studies is that assessments have typically been conducted at a few selected transition points, rather than ongoing throughout the process of BMT. Frequently, there is an initial pre-transplant baseline assessment with no further observation until discharge, with subsequent assessments months later. Such

Acute HRQL in children S Phipps et al

426

an approach may miss acute changes in functioning during the crucial isolation and engraftment period, when somatic and emotional distress are likely to be at a peak. Distress during the acute period of transplant hospitalization, even if transient, may serve as a predictor of later disturbances in quality of life, and may provide an important mechanism for identification of individuals at risk for later impairment. Previous research has also been limited by the lack of appropriate instruments to reliably assess levels of distress, especially within the pediatric population. In a prospective longitudinal study using collateral assessment of children undergoing BMT, Rodrigue et al7 found that parents and nurses had high agreement on reports of children’s behavioral (overt) distress, but moderate agreement on their internal experiences of fear and pain.7 Historically, parents have been relied upon to provide information about their children’s internal states. However, it is becoming increasingly recognized and accepted that children are able to reliably report on their own internal states, including somatic symptoms, pain, and emotional distress.13–16 Therefore, child self-report measures about internal states need to be included to confirm and/or broaden the findings based on collateral reports of children’s internal states made independently by parents and/ or nurses.12,13 To truly understand children’s distress response to BMT, prospective longitudinal studies using valid measures are needed to evaluate changes in distress experienced by pediatric BMT patients throughout each phase of the BMT process. The Behavioral, Affective and Somatic Experiences Scales (BASES) were developed specifically for assessment of acute and short-term outcomes in children undergoing BMT, and provide a set of instruments for assessment of BMT-related distress in children that were previously lacking.17,18 Three versions of the BASES were developed for use in parent, nurse and patient report formats. The BASES consist of five subscales, covering domains labeled Somatic Distress, Mood Disturbance, Compliance, Quality of Interactions and Activity. Together, these scales provide a global composite of acute health-related quality of life (HRQL). Current research in HRQL has generally identified four core domains of functioning that should be assessed in HRQL measures: disease state and physical symptoms; psychological functioning; social functioning; and functional status.19,20 The BASES scales provide analogue measures of these domains that are more appropriate for acute inpatient settings, ie Somatic Distress is an analogue of ‘disease state and physical symptoms’, Mood Disturbance of ‘psychological functioning’, Quality of Interactions of ‘social functioning’ and Activity of ‘functional status’. Thus the BASES provide an appropriate assessment of acute aspects of HRQL for patients undergoing intensive therapy.18 The fifth BASES subscale, ‘Compliance’, is not considered part of the HRQL construct, but is included because it is of particular interest and clinical importance in the BMT setting.1,2,21 In prior reports, the BASES scales have shown good reliability, both in terms of internal consistency and interrater and cross-informant consistency, good discriminative validity, and sensitivity to acute changes over the course of transplant hospitalization.17,18 Multiple methods have been used to assess cross-informant consistency. The identical

Bone Marrow Transplantation

format of parent and nurse report versions allows for calculation of a correlation coefficient between paired observations across all items of the scale. The median correlation (rs) of paired parent–nurse observations measured on day 0 was 0.74, and on day ⫹14 was 0.69. In order to assess child report, scores on the five BASES subscales were obtained and correlated with the comparable subscales on the parent and nurse versions. Cross-informant agreement was highest on the subscales of Somatic Distress (parent– child r ⫽ 0.57, parent–nurse r ⫽ 0.62) and Activity (parent–child r ⫽ 0.43; parent–nurse r ⫽ 0.45), but significant parent–child and parent–nurse correlations were found on all subscales.18 When changes in these BASES indices were tracked over the course of transplant hospitalization, very similar trajectories of change were observed by parent, child, and nurse report.18 In the present paper, we report a prospective, longitudinal study of acute HRQL and compliance in children undergoing BMT, focusing in particular on somatic distress and mood disturbance, since these are of particular clinical interest in an acute inpatient setting. Collateral parent, child and nurse reports were gathered during regular intervals throughout the transplant process from time of hospital admission to 6 months post BMT, thus capturing observations of the acute phase of BMT and transition from hospital to home. Empirical documentation of children’s HRQL and compliance from the time of hospitalization for BMT to 6 months post transplant, based on parent and child report is presented here. (Nurse report data will be presented elsewhere.)

Methods Subjects All children undergoing bone marrow transplantation (BMT) at St Jude Children’s Research Hospital were eligible for inclusion in the study with the exception of those who were non-English speaking or were undergoing BMT due to brain tumor. A total of 187 child patients and their parents were eligible in the period from January 1995 to August 1998. Thirteen of these were missed for inclusion due to extraneous factors that interfered with enrollment prior to hospital admission, and of those approached for participation, only six declined to participate (3.4%). Therefore, a total of 168 child patients and their parents were consecutively enrolled in the study prior to hospital admission for BMT. Of the 168 enrolled, several were inevaluable because they either failed to subsequently be admitted for transplant, became acutely ill very early in the transplant process and were unable to participate further, or were non-compliant in completing study measures. The data presented here are based on a sample of 153 patients/parents who provided baseline data and at least one in-hospital observation. Thus, this study is based upon 82% of eligible patients and their parents. Patients ranged in age from less than 1 year to 20 years of age (mean age 8.9 years) and 54% of patients were male (see Table 1). Representation of socioeconomic status (SES, as determined by the Hollingshead four factor


Table 1

Demographic and medical breakdown of study participants

Gender (male) Age ⬍3 years 3–5 years 6–12 years ⬎12 years Socio-economic status I II III IV V Diagnosis ALL AML Other leukemia Neuroblastoma Other solid tumor Non-malignancy Type of transplant Allogeneic Matched sib MUD Mismatched Family Member Autologous

n

%

84

54.9

42 23 40 48

27.5 15.0 26.1 31.5

10 42 52 28 18

6.7 28.0 34.7 18.7 12.0

23 41 30 16 17 26

15.0 26.8 19.6 10.5 11.1 17.0

102 29 62

66.7 19.0 40.5

11 51

7.2 33.3

ALL ⫽ acute lymphoblastic leukemia; AML ⫽ acute myelogenous leukemia; HD ⫽ Hodgkin’s disease; NHL ⫽ Non-Hodgkin’s lymphoma.

index22) was evenly distributed across low, middle, and high SES groups. The majority of patients (almost twothirds) presented for BMT due to leukemia with the remainder for a variety of solid tumors and non-malignancies, which is representative of the population served by the hospital. The sample includes both patients who underwent allogeneic (66.7%) and autologous BMT (33.3%). For those who underwent allogenic BMT, 28.4% had a matched sibling donor, 10.8% a mismatched family donor, and 60.8% an unrelated donor (MUD). Multiple BMT treatment protocols are represented, using different conditioning regimens, but the majority of allogeneic patients received a regimen containing cyclophosphamide (90 mg/kg), cytarabine (18 gm/m2) and total body irradiation (TBI) to a total of 12 Gy for matched siblings, and 14 Gy for mismatchedrelated and MUDs. A variety of regimens for prophylaxis of GvHD were also used, depending on the protocol and histocompatibility of the donor. An even larger number of protocols were used for patients who underwent autologous BMT, although the most common conditioning regimen included busulfan (16 mg/kg) and cyclophosphamide (200 mk/kg). A total of 57% of all patients received TBI. Instruments The Behavioral, Affective, and Somatic Experiences Scales (BASES): The BASES was initially developed as a nurse report measure of patient response during the acute phase of BMT.17 It is conceptualized as a measure of acute aspects of health-related quality of life (HRQL) for pediatric patients undergoing aggressive treatments, designed

for repeated use and sensitivity to change.18 It contains 38 items (each rated on a five-point Likert scale) in five subscales: Somatic Distress (disease state and physical symptoms, 11 items), Mood Disturbance (affective and psychological functioning, 14 items), Compliance (with medical treatment regimen and self-care, eight items), Quality of Interactions (social functioning, 4 items), and Activity (daily functioning, one item). The instrument has been shown to be internally consistent (␣’s of 0.74 to 0.90) and reliable (median inter-rater r ⫽ 0.86) in prior studies. Further information regarding its development and psychometric properties has been presented elsewhere.17,18 The parent version (BASES-P) used in this study is essentially identical to the 38-item nurse report version, with a few terms re-worded (eg ‘mucositis’ changed to ‘mouth sores’). In pilot studies, paired parent–nurse comparisons yielded a median correlation of 0.56.17 In the current study, internal reliabilities (coefficient ␣ estimated on day ⫹7 were 0.83 for Somatic Distress, 0.82 for Mood Disturbance; 0.73 for compliance, and 0.76 for quality of interactions. As a single item, no internal reliability can be calculated for Activity, but in prior studies, paired interrater reliability on this item was 0.77.17 In the present study, parent–child correlation on this subscale was 0.43. The child report version (BASES-C) of the BASES is briefer, with 14 items rated on the same five-point Likert scale. This shorter version was designed to be as simple as possible for younger children, and to reduce burden when obtaining multiple observations. Data are obtained on the same five subscales as the BASES-P. On the child report data, the internal reliabilities (␣) for Somatic Distress (0.87) and Mood Disturbance (0.76) were adequate. The ␣ for Compliance (0.68) was marginal, but for Quality of Interaction (0.46) it was unacceptable, and we will not report outcomes on this construct by child report. The Activity subscale was again a single item measure.

427

Procedure Patients scheduled to undergo BMT were identified and recruited consecutively for participation 2 to 3 weeks prior to their admission date. For each patient, a ‘resident parent’ was identified, ie the parent who was to remain with the child throughout most of the hospitalization, and would be used consistently as informant. BASES-P data were obtained only from the resident parent, and there was no substitution of respondents. If the resident parent was unavailable for a specific observation, that observation was considered missing. Prior to admission for BMT, child patients were administered an abbreviated neuropsychological screening battery and completed self-report measures to assess pre-morbid levels of self-esteem, personality function, family environment and social support. Resident parents also completed measures on their child’s previous behavioral problems and social competence, family environment and on their own coping behaviors and available support. Following hospital admission, the BASES were administered in a repeated manner to assess child stress responses across the acute phase of BMT. BASES data were obtained by parent, child, and nurse report. Parents and child patients Bone Marrow Transplantation


428

age 5 and older completed the BASES on a weekly basis from time of hospitalization (week ⫺1) to week ⫹6. Weekly data collection was timed to occur on a multiple of the transplant day (ie week ⫹1 ⫽ day ⫹7, week ⫹2 ⫽ day ⫹14, etc.) Collection of BASES-P and BASES-C continued on a monthly basis to month ⫹6 for a total of 13 observations throughout the entire assessment period (weeks ⫺1 to ⫹6, and months ⫹2 to ⫹6). Every effort was made to gather BASES data on the prescribed days as scheduled, however at times, this was not possible. There were instances in which the child was not feeling up to responding or the resident parent was unavailable due to other responsibilities. If data were missed on the prescribed day, attempts were made to collect it on the following day. If it was not possible to gather the data within 2 days of the target, the data were considered missing for that specified time point. Mortality, Attrition, and Missing Data Missing observations were encountered for a variety of reasons, including not only morbidity and mortality, but also due to logistical problems, unavailability of the resident parent, or non-compliance. Six patients had died by week ⫹6, and a total of 35 expired by month 6 (22.9%). Most surviving participants had occasional missing observations distributed intermittantly through the 6 month study period. To week ⫹3, during which time most patients were in hospital, 642 out of 755 possible observations were obtained (85%). At week ⫹6, the frequency of missing data was increased, due to increasing logistical difficulties as patients moved to an outpatient setting. It should be noted, however, that the missing data mean only a missed assessment point and not attrition from the study, as only one patient dropped out of the study entirely. Across the entire study period a total of 1194 observations were obtained from parents and 676 from patients. Statistical methods For analysis of summated scaled scores, which were treated as continuous variables, an unbalanced, repeated measures mixed effects model was utilized,23 which accomodates missing observations using the MIXED procedure in SAS, with the Satterthwaite option for computing degrees of freedom.24 For the analysis of individual items, which are on a five-point ordinal scale, a generalized estimating equations model (GEE) was used via the GEE2 SAS macro.25 Missing and mistimed data were handled in a manner consistent with prior longitudinal studies of HRQL in oncology settings.26–28 Results The results of repeated measures analyses based on 13 assessment points, reflecting changes over time for each of the subscales are presented in Table 2. Based on parent report, highly significant effects and clear patterns of change over time were evidenced on all BASES subscales, as well as on individual BASES items representing specific


symptoms (eg nausea/vomiting, fatigue, sleep disturbance, all P ⬍ 0.0001). Likewise, significant changes were observed by child report on BASES-C subscales. Domain trajectories by parent report Distinct patterns of change in symptoms of distress were observed over the acute BMT transplant period (week ⫺1 to week ⫹3) for all patients. Rather than presenting multiple tables of means, this repeated measures format allows for depicting trajectories of symptomatology over time that may be best appreciated graphically. Outcomes for the BASES subscales by parent report are presented in Figure 1. Following admission, there was a significant increase in Somatic Distress, which peaks a week following transplant (week ⫹1) followed by a rapid decline back to admission levels during weeks 4 to 5 post BMT, with a slower decline to presumed baseline levels in months 4–6 post BMT (Figure 1a). A similar pattern was seen on the BASES domains of Mood Disturbance and Compliance problems. A similar but inverse pattern is seen on Activity (in contrast to other scales, higher values indicate better function for Activity). Therefore, whereas Somatic Distress and Mood Disturbance show a peak at week ⫹1, Activity shows a nadir at this same time point, followed by a rapid improvement (Figure 1d). Patient report and parent–child consistency Patterns of change across the BASES domains by child report are presented in Figure 2. It can be seen that trajectories by parent and child report are very similar, with the minor exception that the patients report their mood to be most disturbed at the time of admission, rather than at week ⫹1 (Figure 2b), but the improvement in Mood Disturbance over time is similar by both respondents. The near-identical trajectory of the Activity scale by both parent and child report is particularly striking. In addition to the similar trajectories reported by both parent and child report, significant correlations between parent and child report were found on all BASES subscales. The median parent– child correlations, across all 13 assessment points, are as follows: Somatic Distress, r ⫽ 0.68; Mood Disturbance, r ⫽ 0.48; Compliance, r ⫽ 0.50; Quality of Interaction, r ⫽ 0.38; Activity, r ⫽ 0.46. Specific symptom trajectories In addition to summarizing scores across acute HRQL domains, individual BASES items can be used to track trajectories of specific symptoms. Some of the most common symptoms within the Somatic Distress domain are presented in Figure 3. Because some of the items, such as nausea and mucositis reflect symptoms for which there is a reasonably predictable trajectory over time, these findings provide additional confirmation of the validity of the BASES measures, and indicate their sensitivity to change on symptoms of interest. As predicted, nausea shows a rapid increase following conditioning, and remains high for the next 3 weeks, followed by a steep decline at week ⫹4. Mucositis shows a sharp peak at week ⫹1 followed by a


Table 2

429

Repeated measures analyses testing change in BASES subscale scores over time Parent report (n ⫽ 151)

Measure

Somatic Distress Compliance Mood Disturbance Quality of Interaction

Activity Nausea/vomiting Mucositis Appetite loss Fatigue/malaise Sad/subdued Fearful/anxious Angry/irritable Sleep disturbance

Child report (n ⫽ 91)

F

df

P

F

df

P

46.28 9.45 7.05 2.11

12,778 12,704 12,862 12,762

0.0001 0.0001 0.0001 0.0001

15.63 9.78 8.04

12,444 12,399 12,438

0.0001 0.0001 0.0001

␹2

df

P

␹2

df

P

182.3 151.8 206.6 285.4 190.3 59.2 40.3 49.6 34.8

12 12 12 12 12 12 12 12 12

0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001

111.4

12

0.0001

b

a

32 25 Somatic distress

Mood disturbance

30 28

20

26

15

24

P < 0.0001 10

-1 0 1

c

22 2 3 4 Week

5 6 2

3 4 5 Month

P < 0.0001 -1 0 1

6

d

2 3 4 Week

5 6 2

3 4 5 Month

6

P < 0.0001

16 4.5 Activity

Compliance

14

4.0

12

3.5 3.0

10 P < 0.0001

-1 0 1 2 3 4 5 6 2 3 4 5 Week Month

6

-1 0 1 2 3 4 5 6 2 3 4 5 6 Week Month

Figure 1 Parent report of BASES Subscales. Trajectories of change over time, from week ⫺1 to month ⫹6 on BASES subscale scores by parent report: (a) Somatic distress; (b) Mood Disturbance; (c) Compliance; (d) Activity.

sharp decline. Fatigue and appetite loss show similar trajectories, with peaks 1–2 weeks following BMT followed by a more gradual return to baseline. Changes in affective symptoms within the Mood Disturbance domain are presented in Figure 4. Anxiety peaks at the time of transplant (day 0) followed by a sharp decline, a stable period and a second sharp decline at week ⫹4, corresponding to the time when the majority of patients are discharged. Peaks in sadness and anger occur at week ⫹1, lagging a

week behind the peak in anxiety. Sleep disturbance shows a steady rise through week ⫹3, followed by a rapid decline, again occurring coincident with the time of discharge for most patients (Figure 4). Discussion Although it has been widely assumed that BMT is a stressful process for children, there have been surprisingly little Bone Marrow Transplantation


a

b

9

9 Mood disturbance

430

Somatic distress

8 7 6 5 4 P < 0.0001 -1 0 1

c

8 7 6 5

2 3 4 Week

5 6 2

3 4 5 Month

6

P < 0.0001 -1 0 1

3 4 5 Month

6

-1 0 1 2 3 4 5 6 2 3 4 5 Week Month

6

d

2 3 4 Week

5

6 2

P < 0.0001

7

Compliance

3.5 Activity

6

3.0

5

2.5

4 P < 0.0001 -1 0 1

2.0 2 3 4 Week

5

6 2

3 4 5 Month

6

Figure 2 Patient report of BASES Subscales. Trajectories of change over time, from week ⫺1 to month ⫹6 on BASES subscale scores by child report: (a) Somatic distress; (b) Mood Disturbance; (c) Compliance; (d) Activity.

b

a 2.6

P < 0.0001

Nausea/Vomiting

2.5

2.2 Mucositis

2.0

1.8

1.5

1.4 P < 0.0001 1.0

-1 0 1

c

1.0 2 3 4 Week

5 6 2

3 4 5 Month

6

d

2 3 4 Week

5 6 2

3 4 5 Month

6

2 3 4 Week

5 6 2

3 4 5 Month

6

4

Appetite loss

Fatigue/Malaise

3.0 2.5

3

2.0 1.5

-1 0 1

2

P < 0.0001 -1 0 1 2 3 4 5 6 2 3 4 5 Week Month

1 P < 0.0001 6

-1 0 1

Figure 3 Parent report of specific somatic symptoms. Trajectories of change over time on specific items from the somatic distress scale: (a) Nausea and Vomiting; (b) Mucositis; (c) Fatigue/Malaise; (d) Appetite Loss.



431

b

a

1.4

1.4 Fearful/Anxious

1.2

Sad/subdued

1.2

1.0

1.0 0.8

0.8

0.6

0.6

0.4 P < 0.0001

0.4 P < 0.0001

-1 0 1 2 3 4 5 6 2 3 4 5 Week Month

6

-1 0 1

d

1.6

1.6

3 4 5 Month

6

2 3 4 Week

5 6 2

3 4 5 Month

6

Angry/Irritable

1.4

1.4 1.2

1.2

1.0 0.8

5 6 2

Sleep disturbances

c

2 3 4 Week

1.0

P < 0.0001 -1 0 1 2 3 4 5 6 2 3 4 5 Week Month

0.8 P < 0.0001 6

-1 0 1

Figure 4 Parent report of specific mood symptoms. Trajectories of change over time on specific items from the mood disturbance scale: (a) Fearful/Anxious; (b) Sad/Subdued; (c) Angry/Irritable; (d) Sleep Disturbance.

empiric data regarding distress and quality of life in pediatric BMT patients across the course of treatment. Most prior reports have been retrospective, or if prospective, have involved very small numbers of patients. The present study represents the first large-scale, prospective, longitudinal evaluation of acute HRQL in children undergoing BMT. For comparison, the only previous report involving pediatric patients that used a similar prospective, repeated measures approach, was based on a total sample of 10 children.7 The repeated measures design of this study is more rigorous, with multiple assessments of patients throughout the acute phase of transplant hospitalization and the subsequent transition period, and allows for tracking of trajectories of change in HRQL, in much the same manner that one might track recovery of neutrophil counts. The major findings from this first descriptive report are summarized as follows: (1) children undergoing BMT appear to enter the hospital with an already heightened level of distress (defined by high levels of somatic symptoms and mood disturbance, and low levels of activity) that increases dramatically following conditioning, reaching a peak approximately 1 week following transplant; (2) this increased distress is transient, declining rapidly back to admission levels by week ⫹4 to week ⫹5, followed by a further decline to presumed basal levels by months 4–6; and (3) the trajectories of distress depicted by both parent and child report are remarkably similar, each providing confirmatory support for the validity of the findings. Many of of the findings presented here serve to confirm widely held clinical impressions that had not been previously documented empirically, ie there are few surprises in the data. It is hardly surprising, for example, that somatic

distress peaks a week following completion of conditioning. In fact, because some of the BASES items, such as mucositis, reflect symptoms for which there was a predictable trajectory over time, the current results provide additional confirmation of the validity of the BASES measures, and confirm their sensitivity to change over time in acute settings. However, the very similar trajectories observed across multiple domains and specific symptoms, with a peak in distress (or conversely a nadir in HRQL) 1 to 2 weeks post BMT followed by a rapid improvement, is perhaps unexpected. More importantly, the trajectories indicate that despite an aggressive program of supportive care, with current generation anti-emetic medications, narcotic analgesics, and a high level of psychosocial support, a considerable amount of distress is still experienced by patients during the acute phase of BMT, involving not only somatic discomfort, but also disturbance in mood, and disruption in behavioral functions. Whether this distress and disruption in HRQL is quantified in terms of peak levels experienced, change from baseline, or some function of area under the curve, there is clear evidence of high levels of distress and thus room for further improvement in supportive care. The transience of these disruptions in HRQL is also striking, with rapid improvement in somatic distress and mood disturbance. Within 4–6 weeks post BMT, distress declined to levels lower than those seen at the time of admission, and a return to a presumed baseline level occurs across all domains within 4–6 months post BMT. This trajectory, with return to baseline in 4–6 months, mirrors the findings presented by Hjermestad et al6 with adult BMT recipients. These findings are also consistent with the only other comBone Marrow Transplantation


432

parable report from pediatric BMT patients.7 The transience of symptoms and rapid decline in distress might be perceived as ‘good news’, and suggestive that the psychological morbidity associated with BMT in children may not be as problematic as many have suspected. However, several cautions are in order. First, although transient, the peaks in somatic distress and mood disturbance seen 1–2 weeks following BMT nevertheless represent a magnitude of distress that is unacceptably high, is potentially reducible, and which may be responsive to additional approaches to intervention. Secondly, the high levels of patient distress may be reflective of an increased physiological stress response which could slow healing and increase medical complications in some patients.29 Just as premorbid psychological functioning has been shown to be predictive of BMT medical outcomes, including toxic complications, length of hospital stay, and even survival,29 the degree of distress during the early engraftment period may significantly influence outcomes, thus highlighting further the need for intervention. Thirdly, the high levels of distress, although transient, may be associated with later disruptions in psychological functioning, such as the disturbances in social competence and self-esteem that have previously been reported in children in the period 6 months to 1 year post BMT,1,30–33 or the development of post-traumatic stress symptomatology,34–36 even after the acute disturbance has subsided. This latter issue raises the question of whether there are multiple trajectories to recovery in BMT that must be considered, and how these relate to each other. Our data illustrate the transient psychological distress that occurs in response to an intensive and demanding medical therapy, and must be distinguished from more persistant problems in psychological adjustment, or frank psychiatric morbidity. The next logical question is whether those patients who experience the greatest distress during the transplant procedure are at higher risk for later disturbances in adjustment. From that perspective, the data from the BASES scales presented here may serve both as an outcome measure – reflecting acute HRQL outcomes – as well as a predictive measure of longer term adjustment outcomes. Many of these questions can be addressed as we continue to follow this longitudinal cohort into the future. The data presented here provide additional validity for the BASES scale as a valid assessment instrument of pediatric HRQL. In particular, it demonstrated sensitivity to changes in somatic distress and mood disturbance across different phases of the BMT procedure. The median parent– child correlations ranged from moderate to high, all were statistically significant, and considerably higher than those typically found with commonly used measures of child behavior and affect.37,38 The similarity of trajectories obtained by both parent and child report also support the validity of the measure. The patterns of peaks and nadirs from the BASES-P and BASES-C are very consistent, and may be the most salient indicator of reliability across informants. The activity score, despite being based on a single item, is shown to be a particularly informative measure. It has good cross-informant consistency, and is highly correlated with other BASES subscales, especially Somatic Distress and Mood Disturbance. Thus it appears to be as


indicative of child distress as any of the other subscales, providing a good global measure of acute HRQL in response to intensive medical treatment. In circumstances where time or instrument burden is a concern, it appears that assessment of activity alone may provide a reasonable estimate of the pediatric patient’s global functioning and acute HRQL. A potential limitation of the present study is that the data analysis is based on the assumption that missing data, due to death, morbidity, or other causes, are missing at random. This is an assumption that is difficult to substantiate, and may not always be met in clinical settings. Missing data have been recognized as an unavoidable problem in longitudinal quality of life research, and a number of approaches to the handling of this problem have been described.26–28 Although there is no uniformly accepted approach to such analysis of ‘messy longitudinal data’, our approach has been described previously and found to be fairly robust.27 Moreover, there is evidence supporting the assumption of random missingness in the present dataset. When participants were divided according to those who had missed five or fewer observations and those missing more than five observations, no differences were observed between these groups on somatic distress. Although not a ‘proof’ of the assumption of missing-at-random, this suggests that there is not substantial evidence against the assumption. Another limitation of the current study is that the dataset, although large, is generated from a single institution. Thus, there are questions regarding the generalizability of the findings. Certainly, approaches to supportive care may vary across institutions, as they will, even across clinicians within the same institution. However, the major approaches to conditioning in pediatric BMT are reasonably comparable across most pediatric centers. Since the intensity of conditioning appears to be a major determinant of patient distress during the acute BMT period, we feel these results are likely to be generalizable to pediatric BMT recipients across institutions. A related issue is how well these findings are likely to apply to pediatric transplant populations in the future, in anticipation of new developments in transplant procedures, such as a shift toward the use of parental haplotype donors, with positive stem cell selection. This will have to be addressed empirically. Fortunately, the relative ease of administration, and general acceptability of repeated use of instruments such as the BASES scales, suggests that the data needed to answer this question could be readily attained. Consideration might be given to inclusion of this or comparable measures as a routine part of patient surveillance during the BMT procedure. This would provide an additional mechanism for monitoring the toxicity of new transplant conditioning protocols as they are developed. The present findings highlight the need for the development of new interventions or more intensive approaches to supportive care aimed at reducing levels of distress during the acute phase of transplant. In light of the finding that levels of distress and mood disturbance are already somewhat elevated at the time of admission for transplant, interventions that begin prior to admission would represent an ideal approach. Unfortunately, pragmatic issues often preclude sufficient contact with patients during the pre-admis-


sion period. Clearly, the time of conditioning and the immediate post-transplant period represent a critical phase, when distress levels are highest, and thus, the opportunities for distress reduction the greatest. The measurement tools utilized here would provide a reasonable approach to assessment of intervention outcomes, and testing efficacy of any interventions in reducing distress or impacting other acute HRQL outcomes. Acknowledgements This work was supported in part by grant R29 CA60616 from the National Cancer Institute, and by the American Lebanese and Syrian Associated Charities (ALSAC).

References 1 Andrykowski M. Pyschiatric and social aspects of bone marrow transplantation. Psychosomatics 1994; 35: 13–24. 2 Phipps S, Barclay D. Psychosocial consequences of pediatric bone marrow transplantation. Int J Pediatr Hematol/Oncol 1996; 3: 171–182. 3 Wettergren L, Langius A, Bjorkholm M, Bjorvell H. Physical and psychosocial functioning in patients undergoing autologous transplantation – a prospective study. Bone Marrow Transplant 1997; 20: 497–502. 4 Leigh S, Wilson KCM, Burns R, Clark RE. Psychosocial morbidity in bone marrow transplant recipients: a prospective study. Bone Marrow Transplant 1995; 16: 635–640. 5 Sasaki T, Akaho R, Sakamaki H et al. Mental disturbances during isolation in bone marrow transplant patients with leukemia. Bone Marrow Transplant 2000; 25: 315–318. 6 Hjermstad MJ, Loge JH, Evensen SA et al. The course of anxiety and depression during the first year after allogeneic or autologous stem cell transplantation. Bone Marrow Transplant 1999; 24: 1219–1228. 7 Rodrigue JR, Graham-Pole J, Kury S et al. Behavioral distress, fear, and pain among children hospitalized for bone marrow transplantation. Clin Transplant 1995; 9: 454–456. 8 Gunter M, Karle M, Werning A, Klingbiel T. Emotional adaptation of children undergoing bone marrow transplantation. Can J Psychiatry 1999; 44: 77–81. 9 Syrjala KL, Chapko MK, Vitiliano PP et al. Recovery after allogeneic marrow transplantation: prospective study of predictors of long-term physical and psychosocial functioning. Bone Marrow Transplant 1993; 11: 319–327. 10 Andrykowski MA, Brady MJ, Greiner CB et al. ‘Returning to normal’ following bone marrow transplantation: outcomes, expectations, and informed consent. Bone Marrow Transplant 1995; 15: 573–581. 11 McQuellon RP, Russell GB, Rambo TD et al. Quality of life and psychological distress of bone marrow transplant receipients: the ‘time trajectory’ to recovery over the first year. Bone Marrow Transplant 1998; 21: 477–486. 12 Parsons SK, Barlow SE, Levy SL et al. Health-related quality of life in pediatric bone marrow transplant survivors: according to whom? Int J Cancer Suppl 1999; 12: 46–51. 13 McConville BJ, Steichen-Asch P, Harris R et al. Pediatric bone marrow transplants: psychological aspects. Can J Psychiatry 1990; 35: 769–775. 14 Garber J, Walker LS, Zeman J. Somatization symptoms in a community sample of children and adolescents: further validation of the Children’s Somatization Inventory. Psychol Assess 1991; 3: 588–595.

15 McGrath PJ. There is more to pain measurement in children than ‘ouch’. Can Psychol 1996; 37: 63–75. 16 McConaughy SH. Advances in empirically based assessment of children’s behavioral and emotional problems. School Psychol Rev 1993; 22: 285–307. 17 Phipps S, Hinds PS, Channell S, Bell G. Measurement of behavioral, affective, and somatic responses to pediatric bone marrow transplantation: Development of the BASES scale. J Pediatr Oncol Nurs 1994; 11: 109–117. 18 Phipps S, Dunavant M, Jayawardene D, Srivastiva D. Assessment of health-related quality of life in acute in-patient settings: use of the BASES instrument in children undergoing bone marrow transplantation. Int J Cancer Suppl 1999; 12: 18–24. 19 Spieth LE, Harris CV. Assessment of health-related quality of life in children and adolescents: an integrative review. J Pediatr Psychol 1996; 21: 175–193. 20 Testa MA, Simonson DC. Assessment of quality of life outcomes. New Engl J Med 1996; 334: 835–840. 21 Phipps S, Decuir-Whalley S. Adherence issues in pediatric bone marrow transplantation. J Pediatr Psychol 1990; 15: 459–475. 22 Hollingshead AB. Four Factor Index of Social Status. Yale University Press: New Haven, CT, 1975. 23 Diggle PJ, Liang KY, Zeger SL. Analysis of Longitudinal Data. Oxford University Press: New York, 1994. 24 SAS Institute, Inc. SAS OnlineDoc, Version 8. SAS Institute Inc: Cary, NC, 1999. 25 Lipsitz SR, Kim K, Zhao L. Analysis of repeated categorical data using generalized estimating equations. Stat Med 1994; 13: 1149–1163. 26 Fairclough DL, Peterson HF, Chang V. Why are missing quality of life data a problem in clinical trials of cancer therapy? Stat Med 1998; 17: 667–677. 27 Qian W, Parmar MKB, Sambrook RJ et al. Analysis of messy data from a randomized clinical trial. Stat Med 2000; 19: 2657–2674. 28 Fairclough DL, Peterson HF, Cella D, Bonomi P. Comparison of several model-based methods for analysing incomplete quality of life data in cancer clinical trials. Stat Med 1998; 17: 781–796. 29 Sullivan AK, Szkrumelak N, Hoffman LH. Psychological risk factors and early complications after bone marrow transplantation in adults. Bone Marrow Transplant 1999; 24: 1109– 1120. 30 Phipps S, Brenner M, Heslop H et al. Psychological effects of bone marrow transplantation on children: preliminary report of a longitudinal study. Bone Marrow Transplant 1995; 16: 829–835. 31 Phipps S, Mulhern RK. Family cohesion and expressiveness promote resilience to the stress of pediatric bone marrow transplant: a preliminary report. Dev Behav Pediatr 1995; 16(4): 257–263. 32 Vannatta K, Zeller M, Noll RB, Koontz K. Social functioning of children surviving bone marrow transplantation. J Pediatr Psychol 1998; 23: 169–178. 33 Barrera M, Pringle LAB, Sumbler K, Saunders F. Quality of life and behavioral adjustment after pediatric bone marrow transplantation. Bone Marrow Transplant 2000; 26: 427–435. 34 Stuber M, Nader K, Yasuda P et al. Stress responses following pediatric bone marrow transplantation: preliminary results of a prospective longitudinal study. J Am Acad Child Adolesc Psychiatry 1991; 30: 952–957. 35 Butler R, Rizzi L, Handwerger B. The assessment of posttraumatic stress disorder in pediatric cancer patients and survivors. J Pediatr Psychol 1996; 21: 499–504. 36 Stuber M, Kazak A, Meeske K, Barakat L. Is posttraumatic

433



434

stress a viable model for understanding responses to childhood cancer? Child Adolesc Psychiatry Clin NAm 1998; 7: 169– 182. 37 Achenbach TM, McConaughy SH, Howell CT. Child/ adolescent behavioral and emotional problems: implications of


cross-informant correlations for situational specificity. Psychol Bull 1987; 101: 213–232. 38 Klein RG. Parent–child agreement in clinical assessment of anxiety and other psychopathology: a review. J Anxiety Dis 1991; 5: 187–198.