The current study examined a multi-site trial of complementary therapies designed to reduce distress and improve well-being in pediatric patients undergoing SCT. Contrary to hypothesis, the trial produced largely null findings, and no clear evidence of benefit for either the child-targeted intervention alone, or in combination with a parent-targeted intervention. On the primary outcomes of patient and parent reported somatic distress, mood disturbance, and activity levels as captured on the BASES scales, there were no differences in mean distress relative to baseline (area under the curve) and the longitudinal trajectories of the three groups were remarkably similar. The only marginally significant effect was seen for positive affect, where the HPI-C intervention group reported lower levels of overall positive affect across the study period compared to the SC or HPI-CP groups. However, this was due primarily to differences at baseline, as there were no group differences in longitudinal trends. Regarding medical outcomes, there were no significant intervention effects observed on length of hospitalization, time to engraftment, or use of analgesic or antiemetic medications.
This study was designed to detect a difference of 0.45SD between the SC group and intervention groups (HPI-C or HPI-CP) in the area under the curve mean scores on the BASES scales from week -1 to week +3, at α = .05 with 80% power. Because of a somewhat smaller sample at study entry and further reduction in N from missing data, power was reduced such that there was 80% power to detect an effect size of .55SD, generally considered a moderate effect. Thus it is possible that the null findings reflect lack of sufficient power to detect smaller group differences. Descriptively however, the observed effects were quite small, with effects sizes between the SC and HPI_C groups of .05 on BASES child report; .07 on BASES parent report, and -.22 on the PANAS-C. Similarly, effect size for comparisons between SC and HPI-CP were .04 for BASES child report, .24 for BASES parent report, and -.15 on the PANAS-C. These effects are of a magnitude that we would not consider clinically relevant.
The absence of significant intervention effects is disappointing and somewhat surprising, in light of prior studies of complementary therapies in adult transplant settings, as well as our own pilot studies.16-21
This compels an examination of factors that might have contributed to this lack of intervention effects. One issue is whether the most appropriate outcome measures have been assessed. It was the anecdotal impression of study staff, based on observation and patient/parent report, that those receiving the intervention were experiencing benefits. However, when objective, repeated measures were obtained, no evidence of benefits was seen. Certainly, it is possible that there are relevant outcomes that were not measured, but the BASES scales were developed specifically for the purpose of measuring transplant-related distress, and were shown to be sensitive to change over time in this study. Thus the null findings cannot be attributed to measurement insensitivity. Moreover, the absence of group differences on the medical outcomes of days in hospital, time to engraftment, and medication usage, is consistent with our null findings on self-report outcomes, and point to the conclusion that the interventions did not produce their intended effects.
The timing of our measurements is another potential issue. In many prior studies of complementary therapies, particularly massage, measures have been obtained pre- and immediately post-intervention.16-19, 22-25
The immediate effects of massage in reducing reports of anxiety and pain are well established.22,25
However, these effects appear to be relatively short-lived, and may not reflect the sustained effects of intervention, nor the cumulative effect of repeated interventions over the course of transplant hospitalization, which was our primary focus. The current findings do not demonstrate significant sustained effects of the interventions. Patient and parent perception of benefit may not reflect actual positive change, a trend which has been found previously with massage in the transplant setting.40
Another factor that may have contributed to the null findings is the relatively low levels of distress in the sample overall. Although there were clear longitudinal trends observed, with a peak in distress around week +1 as reported in our prior natural history studies9,10
, the absolute levels of distress were surprisingly low, and the amplitude of change from admission to peak levels was smaller relative to prior reports. Perhaps improvements in standard supportive care have led to continued decreases in distress such that it is more difficult to demonstrate effects. This is not to say that transplant-related distress has been eliminated, but that it may be difficult to reduce distress further beyond that of current aggressive standard care.
The current interventions were designed to reduce acute distress during the early and most intense phase of transplant. Given recent concerns regarding posttraumatic stress and other potential psychosocial late effects, perhaps the impact of the intervention may become more measurable over time despite the apparent absence of effects during the acute phase. The current design included follow-up through 6-months post-transplant. The effects of the intervention on more global quality of life and adjustment outcomes at 6-months are currently being examined.
There are some study limitations which deserve mention. The age range of 6-18 years is rather broad, and required some developmental tailoring which reduced standardization, particularly for the humor intervention. There were also potential regional differences that required flexibility and thus less standardization in regard to the humor materials. Differences in practice, and in availability of patients prior to admission for transplant led to variation in timing of baseline assessements both across and within sites. The study design required the baseline assessment to be completed prior to randomization in all cases. However, this may have occurred on the day of admission for some patients and one to two weeks prior to admission for others. As in most repeated measures studies in clinical settings, we also experienced missing data. Across the course of the study, 27% of possible observations were missed. Our statistical models assume data were missing at random, an assumption that is rarely met. However, our rate of missing data is similar to that of other studies with comparable designs, including our prior studies in the same setting, and more importantly, the rate of missing data did not differ across treatment arms.
Certainly, there may be other design elements and limitations that could have hindered our ability to detect intervention effects. However, overall study compliance was good, and treatment integrity procedures suggest that most participants received the majority of the intended interventions, and in an adequate/appropriate manner. The null findings reported here are not sufficient to yield a conclusion that massage and humor therapy are ineffective in the pediatric transplant setting. This is a single trial and other trials are necessary before any such generalization should be made. As mentioned previously, our study was not adequately powered to detect small effects. We are aware of other trials that are currently underway, and remain hopeful that benefits may be more clearly demonstrated. In the meantime, complementary therapies such as massage are becoming more widely available and offered as supportive care in many major cancer centers.43 Should oncologists and transplant physicians be recommending these approaches? Such therapies are relatively inexpensive to provide, are perceived positively by patients, and while not completely without risk, when provided by trained practitioners are generally safe and involve minimal risk of significant harm. In three studies involving massage, we have yet to experience a single adverse event. At the same time, the measurable benefits of such therapies in settings such as SCT have yet to be clearly documented. The current trial does not provide support for the benefits of massage and humor therapy in reducing distress in the pediatric SCT setting, and suggests some caution in the widespread application of these therapies.