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Journal of Clinical Oncology, Vol 25, No 27 (September 20), 2007: pp. 4239-4245 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.08.7684 Reduction of Health Status 7 Years After Addition of Chemotherapy to Craniospinal Irradiation for Medulloblastoma: A Follow-Up Study in PNET 3 Trial Survivors—on Behalf of the CCLG (formerly UKCCSG)
From the Departments of Child Health and Research and Development Support Unit, University of Southampton, Southampton; and the London Centre for Paediatric Endocrinology, University College London, London, United Kingdom Address reprint requests to Colin Kennedy, MBBS, MD, Mailpoint 803 C/B, University Department of Child Health, Southampton General Hospital, Southampton, SO16 6YD, UK; e-mail: crk1{at}soton.ac.uk
Purpose To compare quality of survival after craniospinal irradiation (CSI) alone with survival after CSI plus chemotherapy (CT) for medulloblastoma. Patients and Methods Follow-up study of surviving UK patients with medulloblastoma diagnosed between 1992 and 2000 treated according to one or other treatment arm of the PNET 3 controlled trial. Results Seventy three percent of all 147 eligible patients ages 6.6 to 24.3 years were assessed at a mean of 7.2 years after diagnosis. Health status was significantly poorer in the group treated in the CSI plus CT arm of the trial than in the CSI alone arm, and there were also trends to poorer outcomes for behavior and quality of life scores. The CSI plus CT group were also significantly more restricted physically and needed more therapeutic and educational support. Body mass index, stature, and other endocrine outcomes were similar in the two treatment arms, except for the trend in increased frequency of medical induction of puberty in the CSI plus CT group. Conclusion The addition of CT to CSI for medulloblastoma was associated with a significant decrease in health status. The effect of the addition of other CT regimens to CSI on quality of survival should be evaluated.
Three phase III–controlled trials of treatment for medulloblastoma, the most common malignant brain tumor of childhood, have been reported in Europe: International Society of Pediatric Oncology (SIOP) 1, SIOP 2, and PNET 3.1-3 A modest trend to survival advantage was associated with allocation to craniospinal irradiation (CSI) plus chemotherapy (CT) rather than to CSI alone in SIOP 1,1 as in the American Children's Cancer Group 9424 trial, and in PNET 3. In the latter study, a CT regimen before CSI was compared with CSI alone for patients with standard-risk medulloblastoma. Five-year event-free survival for medulloblastoma was significantly better in the CSI plus CT treatment arm compared with the CSI alone arm (74.2% v 59.8%), though there was no significant difference between the two treatment arms in overall survival (76.7% v 64.9%).3 The present study considered the quality of survival in children achieving disease-free survival 7 years after treatment for medulloblastoma in the PNET 3 trial. The addition of CT to CSI has in the last decade been regarded as the standard of care for this tumor—a view that rests on better than historically anticipated survival in several single-arm studies5-7 rather than the controlled trials described previously. Consequently, almost all recent clinical trials for medulloblastoma over this period, with the exception of the European trials, have compared the effect of two different regimens of CSI plus CT on survival rather than comparing CSI alone with CSI plus CT. Over the same period, the proportion of survivors has increased, and greater efforts have been made to assess their quality of survival. A reduction in the dose of CSI has been associated with a significant benefit to cognitive abilities in cross-sectional but not in longitudinal studies.5,8,9 Other reports of quality of survival after surgery for posterior fossa tumors have highlighted a strong association between persistence of postoperative cerebellar deficits, particularly akinetic mutism, and poorer neurocognitive outcome,10,11 but many studies have lacked information about pre- or postoperative neurological function.8,9,12-15 A potentially toxic effect of CSI plus CT, additional to that of CSI alone, on central growth hormone secretion16 and at gonadal,17 thyroid,18 and skeletal19 sites has been observed in cross-sectional studies. However, the effect of the addition of CT to CSI on other aspects of quality of survival after medulloblastoma has not been systematically assessed. The present study afforded a rare opportunity to examine the effect of the addition of CT to CSI on quality of survival, defined as health status, behavior, and quality of life.
Design A multicenter follow-up study was undertaken from September 2001 to August 2004.
Patients
Outcome Measures
Procedure The protocol for this study was approved by the members of the UKCCSG and by the Trent Multicenter Research Ethics Committee in the United Kingdom. Written informed consent was obtained from all participating parents and children.
Statistical Analyses
Of the 346 UK patients enrolled from 1992 to 2000 in the original SIOP PNET 3 treatment trial, 277 had a medulloblastoma (144 treated with CSI, 133 with CSI plus CT). Of these, 147 remained alive without active disease in 2001 to 2004, the period of the present study. Eight were untraceable, and 139 were invited to participate. Of these, 21 did not respond, 10 declined, and 108 (73%) accepted the invitation at a mean interval after diagnosis of 7.2 years (Table 1). Participants were similar to nonparticipants with respect to pre- and postoperative neurological characteristics and a similar percentage of eligible patients from the two treatment arms (71% and 78%) participated in the study (Table 1).
Pre- and Postoperative Characteristics Participants’ pre- and postoperative neurological status was similar comparing those allocated treatment randomly to those in whom it was allocated nonrandomly and comparing those treated with CSI alone with those treated with CSI plus CT (Table 1), though a nonsignificant excess of postoperative mutism in the CSI plus CT group might have been clinically important (see Discussion). Family demographic characteristics of those treated with CSI alone and CSI plus CT were also similar (Table 2).
Outcomes at Post-Treatment Evaluation Considering both adults and children as a single group for the purpose of assessing health status, lower overall HUI3 utility self-report scores were observed in the CSI plus CT group than in the CSI group (n = 38 and 59; median scores, 0.71 and 0.93, respectively; mean difference, –0.15; 95% CI, –0.03 to –0.27; P = .003) and a similar trend was seen in proxy-report scores (Table 3). These differences were accounted for by lower subscores in the CSI plus CT group for dexterity by proxy-report, and for ambulation and speech levels by self-report.
Using the SDQ as a measure of behavioral difficulties, there was a trend to higher (ie, poorer) Total Difficulties scores by proxy-report, but not by self-report, in the group treated with CSI plus CT than in the CSI alone group (Table 3). Similarly, quality of life measures in the same age group showed strong trends to poorer scores by proxy-report in the group treated with CSI plus CT compared with the CSI alone group, both on the PedsQL total score (accounted for by an underlying difference in the emotional symptoms subscores) and also on the CHQ-PF28 physical summary scores (accounted for by an underlying difference in physical functioning and limitation of social/role functioning because of emotional or behavioral difficulties, physical health, and bodily pain; Table 3). These lower summary scores were associated with greater limitations on the amount of time parents had for their own needs and a greater impact on family activities. Global health scores for the QLQ-C30 quality of life measure (18 to 24 year olds) were similar in the two treatment arms (Table 3) as were the other QLQ-C30 functioning scales (not shown). The accompanying BN20 module, designed specifically for adults treated for brain tumors, showed increased motor difficulty in the CSI plus CT group compared with the CSI alone group (Table 3) but the two treatment groups had similar scores on the other BN20 functioning scales (not shown). Because of the possibility of unknown confounding in patients whose treatment was allocated by parent/physician choice, we repeated this primary outcome analysis in the subgroup that was allocated treatment randomly (n = 50). This group also showed a trend to poorer outcomes in the CSI plus CT group relative to the CSI alone group with an intergroup difference of –0.17 on HUI3 by self-report (P = .053). To avoid confounding by postoperative mutism, we also repeated the primary outcome analysis after excluding those in whom postoperative mutism was either present (n = 11) or not recorded as absent (n = 10). This group (n = 83) also showed a trend to poorer outcomes in the CSI plus CT group relative to the CSI alone group with an intergroup difference of –0.11 on the HUI3 by self-report (P = .094; Table A1, online only).
Interrelationships Between Primary and Secondary Outcomes
At 7 years after enrollment in the SIOP PNET 3 trial, survivors who had received CT before CSI had significantly poorer health status by self-report and showed trends to more behavioral and emotional problems and poorer quality of life by proxy-report than if they had received CSI alone. These findings were supported by increased need for physiotherapy and educational support. The relatively high participation rate (73%) reduces the chance of selection bias. A difference in health status equivalent to a change in HUI2 or HUI3 overall scores of 0.03 or more is regarded as clinically important.31 The intergroup difference in HUI3 scores of 0.15 by self-report is, therefore, clinically substantial. Because the CIs do not include 0.03, there is strong evidence (95% CI) that the true intergroup difference is greater than 0.05. In the subgroup that received treatment by random allocation and also in that without postoperative mutism, these mean intergroup differences remained clinically important (0.21 and 0.11, respectively). An intergroup difference in quality of life of 6.5 on the PedsQL proxy-report total score also exceeded the published threshold of 4.5 for a clinically important difference.25 A comparable threshold for scores on the CHQ-PF28 scores is not yet clearly established in the United Kingdom. The SDQ, a screening measure of behavioral difficulties for psychiatric caseness is expected to identify 10% as borderline and 10% as abnormal in a community sample (www.sdqinfo.com). Compared with allocation to CSI alone, allocation to CSI plus CT was associated with little change in the percentage classified on this measure by parental report as borderline (15% v 17%), but a substantially higher percentage (37% v 14%) of abnormal scores. The problem of multiple comparisons is particularly acute in assessing quality of survival. We have taken this into account by reporting, as currently recommended,32 unadjusted P values and confidence limits while exercising caution with respect to interpretation by choosing P < .01 as the criterion of statistical significance. Among the outcomes measured, only the HUI3 was applicable across the entire age range. Our comparisons on other measures were increased in number and also reduced in power because of the need to consider adults and children separately. The trend to worse outcomes in the CSI plus CT treatment arm is apparent on every outcome measure (Table 3), suggesting a genuinely inferior quality of survival in this group. Participants who were allocated to CSI or CSI plus CT by parent or physician choice had similar baseline characteristics before adjuvant therapy compared with those who received these treatments by random allocation. However, confounding, as a result of some unknown factor being related both to these choices and also to quality of survival, cannot be excluded. This is a limitation of this study, notwithstanding the emergence of similar patterns of intergroup differences in the randomly allocated subgroup. Prospective recording of pre- and postoperative neurological status and the inclusion of growth and endocrine outcomes, which have been lacking in many previous reports of the effect of variation of treatment (eg, dose of CSI) on neurocognitive outcome following medulloblastoma,8,9,12-15 is a strength of this study. The pre- and postoperative neurological features were, with the exception of hydrocephalus, categorized only as present or absent and this limited our ability to assess their likely influence on subsequent outcomes. The (statistically nonsignificant) excess of postoperative akinetic mutism, among those allocated to CSI plus CT, compared with those allocated to CSI alone, presumably occurred by chance. However, its presence has, in other studies, been reported to be predictive of poorer long-term neurocognitive outcomes10 and may, therefore, have contributed to the poorer outcomes in the CSI plus CT group. Adjustment for pre- and postoperative adverse features in a multivariate analysis of variance or a regression model was precluded by inequality of variance between the groups and non-normality of the distribution of outcome scores and of residual variance after modeling. However, an adverse effect of CSI plus CT not attributable to akinetic mutism was suggested by the existence of a similar pattern of intertreatment group differences in the subgroup in which the absence of akinetic mutism had been recorded. The outcome was similar in both treatment arms with respect to hormonal deficiencies and consequent hormonal replacement therapy, except for an increased likelihood of requiring pubertal induction after CSI plus CT than after CSI alone, as reported by others.17 Cyclophosphamide has dose- and sex-dependent gonadotoxicity,33 but the true magnitude of the difference between treatment arms with respect to the long-term need for estrogen support to maintain pubertal progress and menstrual rhythmicity, and subfertility may, however, be underestimated in this study because of under-recognition of pubertal delay in girls, who are more vulnerable to this toxicity than boys.17,18 The girls in the study, one third of the sample, were not all postpubertal when assessed. Longer follow-up is required to determine whether these and other (eg, cognitive) differences increase over time in our sample, as reported by others.13,14 Increased incidence of obesity has been described after CSI for leukemia,34,35 and our patients, who received higher doses of CSI than those used for leukemia, were fatter and heavier than the healthy population in 1990,30 though these follow more recent epidemiological trends.36,37 They were also shorter than the 1990 healthy normative values, despite growth hormone replacement therapy, probably because of CSI-induced restriction of spinal growth, as previously reported in similar samples.38,39 Although we did not measure sitting height nor serum thyrotropin, the similar body heights and rates of thyroxine therapy requirement in the two treatment arms do not support previous reports of greater spinal shortening19 and more frequent hypothyroidism18,38 in children given CSI plus CT than those given CSI alone. Endocrine factors, therefore, cannot be invoked as the explanation of the differences observed in this study between treatment arms with regard to health status and quality of life. The mechanism of the association between these adverse effects and prior treatment with CSI plus CT is unclear. Increased restriction of physical activity and behavior problems and need for special educational support provision, combined with decreased quality of life would not be expected as long-term consequences of CT alone, though this has not previously been systematically assessed. We found no evidence of substantial CT-induced auditory dysfunction or a change in the illness experience associated with the addition of CT to CSI that could account for the poorer quality of survival observed in the CSI plus CT group. We have no reason to suppose that renal, cardiac, or lung function differed between treatment arms, but did not formally assess them. The adverse effects of addition of CT may perhaps have arisen as a result of both vincristine neuropathy and radiosensitizing effects of one or more of the CT agents, even though given sequentially rather than simultaneously with CSI. Current CSI plus CT regimens often employ more prolonged or intensive regimens of CT than were received by patients in this study and include therapy with CT that is simultaneous with CSI, albeit with lower doses of CSI in some instances and their CT-related toxicity would be expected to be at least as great as that induced by the PNET 3 regimen of CT. The relationships between dose of CSI, choice and intensity of CT, and the order of and time interval between CT and CSI, and their combined adverse effects at different ages and follow-up intervals require further study. Higher survival rates in current studies than in PNET 3 may in themselves be associated with better or worse quality of survival in the surviving group, depending on the reasons for improved survival rates, but this can only be assessed in participants in those studies. Improved survival rates in medulloblastoma have been attributed to the addition of CT to CSI, but alternative explanations include improved technique and quality assurance of neurosurgery and radiotherapy and/or more rigorous exclusion of high-risk cases. By contrast, unwanted effects of treatment on quality of survival have been attributed to CSI, even though data on the unwanted effects of adding CT to CSI are lacking. Our study suggests a significant role of CT in aggravating adverse effects of CSI, but also highlights the potential relevance of pre- and postoperative neurological status. Our observations in this exploratory study require confirmation in other populations. Our findings suggest the need for further investigation of the potential for adverse effects of current treatment regimens, particularly those using more intensive or prolonged combinations of CT with CSI.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: N/A Research Funds: Kim S. Bull, Samantha Dickson Research Trust Testimony: N/A Other: N/A
Conception and design: Helen A. Spoudeas, Colin R. Kennedy Administrative support: Kim S. Bull Collection and assembly of data: Kim S. Bull Data analysis and interpretation: Kim S. Bull, Helen A. Spoudeas, Ghasem Yadegarfar, Colin R. Kennedy Manuscript writing: Kim S. Bull, Helen A. Spoudeas, Ghasem Yadegarfar, Colin R. Kennedy Final approval of manuscript: Kim S. Bull, Helen A. Spoudeas, Ghasem Yadegarfar, Colin R. Kennedy
Interrelationships Between Primary Outcomes There were strong positive correlations (0.65 to 0.73) between proxy-report and self-report scores whether of health status, behavioral difficulties, or quality of life; moderate positive correlations (0.40 to 0.51) between health status and quality of life scores; and fair to moderate negative correlations (–0.25 to –0.58) between behavioral difficulties and both health status and quality of life scores (Table 4). Age at diagnosis correlated positively with health status (0.24) and quality of life (0.31) and negatively with behavioural difficulties (–0.27). Time elapsed since diagnosis did not correlate with health status, severity of behavioral difficulties, nor with quality of life. Age at assessment correlated positively with health status (0.23) but not with any of the other outcome measures.
Secondary Outcomes Physiotherapy, psychology, and special educational services had been provided for a significantly higher proportion of those patients in the CSI plus CT group (Table 6). Although fewer in the CSI plus CT group had achieved educational examination passes at grade A to C at 16 years, this fell short of statistical significance in the subgroup that had reached that age (Table 6).
We thank Sue Ablett, Chris Eiser, Adam Glaser, Linda Lashford, Catherine Law, Gill Levitt, Mark Mullee, Barry Pizer, Kath Robinson, David Walker, the UK Children's Cancer Study Group (now Children's Cancer and Leukemia Group) members and research nurses at treatment centers and, above all, the patients and parents.
Supported by the Samantha Dickson Brain Tumour Trust and the UK Children's Cancer and Leukaemia Group. Samantha Dickson Brain Tumour Trust supported all study costs, but was not involved in the study conception or design; data acquisition, analysis, or interpretation; report writing; or the decision to submit the paper for publication. Presented in part at the 11th International Symposium on Pediatric Neurooncology, June 13-16, 2004, Boston MA; Société Internationale d'Oncologie Pédiatrique Brain Tumor Committee, June 9-11, 2005, Tromsø, Norway; and the British Paediatric Neurology Association Annual Scientific meeting, January 18-20, 2006, Bristol, United Kingdom. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2, t test, and the Mann-Whitney U test were used as appropriate with two-tailed significance values using SPSS version 14.0 (SPSS Inc, Chicago, IL). Only total, global, or summary outcome scores (except the BN20, which produces only domain scores) were examined. When a difference was found, its locus was sought by analysis of component domain scores. To adjust for multiple testing, P < .01, rather than P < .05, was chosen as the threshold for statistical significance. 
