Journal ofNeuro-Oncology 22: 67-76, 1994. 9 1994KluwerAcademicPublishers. Printedin the Netherlands. Clinical Study

Scale for assessing quality of life of children survivors of cranial posterior fossa tumors Jose Martinez-Ciiment 1, Victoria Castel Sanchez, Carlos Esquembre Menor, Amparo Verdeguer Miralles and Josep Ferns Tortajada 'La Fe' Children's Hospital, Pediatric Oncology Unit, Avda. Campanar, 21, 46009 Valencia, Spain," l Current address: The University of Chicago Medical Center, Section of Hem/Oncology, Chicago, Il, USA

Key words: quality of life, children, brain tumors, posterior fossa tumors, long-term sequelae, astrocytoma, medulloblastoma, brain stem glioma, ependymoma Abstract

Background. Evaluation of quality of life of survivors of brain tumors is an important aspect of outcome that must be included in clinical studies. Methods. We have developed a new scale for assessing quality of life (QL) of pediatric long-term survivors of posterior fossa tumors based on their physical, psychointellectual~ and endocrine/growth status. We have studied 39 patients, with a median follow-up of 9 years. Twenty-five had cerebellar astrocytoma (CA), 6 medulloblastoma (MDB), 5 brain-stem glioma (BSG) and 3 ependymoma of IV ventricle (EPD). Results. Sixty-six percent of children showed neurologic and/or visual sequelae. Little or no significant disability (Bloom's levels I-II) were present in 66%. Psychointellectual dysfunction was present in 44%, with an IQ < 90 in 39%. Endocrine and growth disorders were ~ound in 26%, mostly stature anomalies. According to our scale, QL scores were high in 19 patients (49%), intermediate in 8 (20%), and low in the remaining 12 (31%). Unfavourable outcomes were related to age of less than 4 years, tumors other than CA (MDB, BSG, EPD), incomplete tumoral resection, and employment of radiotherapy and chemotherapy. Conclusion. Our results are comparable to others pre~4eusly reported, and this supports the validity of our scale. We consider that this scale is applicable to evaluate QL of children survivors of cranial tumors.

Introduction

Intracranial tumors account for 20% of all childhood cancers, exceeded only by leukemias. More than half are located in the posterior fossa, essentially low-grade cerebellar astrocytomas and medulloblastomas, and less frequently brain-stem gliornas and ependymomas [1, 2]. Survival of children with brain tumors has increased over the last two decades, due in part to ad-

vances in neurosurgery, radiation, and chemotherapy [2--4]. However, as a consequence of these aggressive therapies, the long term evolution of children cured of brain tumors is far from being satisfactory [5-9]. Studies assessing quality of life (QL) of these survivors are often difficult~ mainly because of the broad spectrum of sequelae they develop [10-12]. The present study was designed to quantify these long-term sequelae and evaluate QL of pediatric

68 survivors of posterior fossa tumors (PFT). For this purpose, we have developed a new scale based on evaluation of functional, psychointellectual and endocrine/growth status after treatment. We have based our scale on previously published papers and our own experience [13-23].

Methods:

study

design

Phase L Subjects

Charts of all children survivors of PFT seen at our Unit from March 1971 to March 1988 were reviewed. Details of tumor and patient characteristics were abstracted. Subjects who fulfilled the following criteria were included: - younger than 11 years at diagnosis. - no neurological, visual, psychointelectual or endocrine deficit before diagnosis. - at least 3 years of follow up from diagnosis when evaluation was done, with no sign of tumor activity since remission had been achieved. - patient and families consent to participate in the study.

Phase II. Evaluation of patients

Thirty-nine patients were evaluated and included in the study. The following parameters were determined: l. Physical and neurological status Formal examination by a pediatric oncologist which included assessements of the patient's motor, somatosensory, oculomotor, auditory, and cerebellar functions was conducted. Ophthalmoscopic evaluation, quantification of visual acuity with the Snellen chart (in younger children picture optotypes were used), and visual field testing with Goldman visual field were performed in all patients by a pediatric ophthalmologist. Also investigated was whether patients had normal or handicapped physical activity (sports, play, dance). Patients were classified according to their degree of disability as recommended by Bloom (Table 1) [24].

2. Psychological functioning

All subjects, as well as one or both parents, were interviewed in person. Verbal, learning, perceptual and memory abilities of subjects were assessed. Educative or occupational levels were measured as Good-Fair-Poor. Mental disabilities, behavioral unadaptability, emotional problems, or depression were registered. If any of these problems were detected, the patients were reevaluated by a pediatric psychologist. Practice of spare time activities (manual skills, music, reading, painting) were tested. Intelligence tests were performed: the Weschesler Intelligence Scale (WISC) was used in children from 4 to 15 years, the WISC for adults (WAIS-R) was used in older patients [25], and the TermanMerril test was used test in children younger than 4 years [2@ 3. Growth and endocrine status The following parameters were determined: height, weight and height velocity according to Tanner [27]. upper/lower segment ratios, measured by determining total height and pubis-to-floor length [28]. - bone age by standards of Greulich-Pyle [29]. - puberal status (Tanner), menarche and sexual development. According to these evaluations, patients were classified into three levels of endocrine and growth status: * level 1: patients with no endocrine or growth sequelae. * Level 2: patients with one of the following endocrine or growth sequelae: normal stature with decreased height velocity, obesity with weight percentile > 90, reduced upper/lower segment of height ratio, or retarded bone age. * Level 3: patients with precocious puberty, paTable 1. Bloom'sscale

Level I: Level II: Level III: Level IV:

No disabilities,active life Mild disability,active life Moderate disability,capable of self-care Total disability,incapable of self-care

69 tients with percentile of height < 3, or patients with two or more of the sequelae included in Level 2. In cases of growlh or endocrine disorders, stimulation tests for measuring the pituitary function were performed: growth hormone (GH) provocation test with insulin (0,1 U/kg i.v.) (normal response: serum GH > 7 ng/mL at any time); FSH and LH levels afte~ LP/-RH infusion (lO9 mcgr i.v.) (non;na~ vMues LH: 15-55 ng/mL; FSH: 0-280 ng/mL; nmmal response: doubling the baseline LH, 0-30% rise in FSH); and T3, T4 and TSH concentrations after TRH infusion (200 mcgr i.v,) (normal value~ T3: 75-200 Ixg/dL; T4:5-11 ~g/dL; TSH: 0.5-3.8 i_tUt mL; normal response: TSH rinse of 5 gU/mL above baseline) [30].

The basis for differentiating the four groups of patients was their degree of disability and their QL after rehabilitation: * Group A (13 poinls): No disabiliw, very good QL. * Group B (11,12 points): Minor disability, acceptable or good QL. * Group C (8-10 points): Moderate disability, acceptable QL after adequate rehabilitation. + Group D (< 8 points): Severe disability, poor QL. Finally, the QL scores were evaluated with respect to patient's characteristics, as well aa therapy. Statistical methods

The association of the diverse sequelae and the QL scores among subgroups of patients were assessed by Fisher's exact test. All values were tested for one

Phase IlL Quality-of-l~fe scale

The scale for asgessing QL is represented in Table 2. Table 2. Scale for assessing quality of life of children survivors of brain tumors L Functionalstgtus (Bloom's scale) - Level Level - Level - Level -

I ............................................. II ........................................... III .......................................... IV ..........................................

4 Points 3 Points 1 Point 0 Points

Table J. Characteristics and therapy of 39 children survivors of posterior fossa tumors * Median age at diagnosis: 5 years (range 1-10 years) * Median age at evaluation 14 y (range 4-23 years) * Median foBow-up time: 9 y (r~nge 3-29 years) * Sex: 17 males/22 females * Type and location of tumor: Cerebellar astrocytoma ...................................... 25 Medulloblastoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Brain stem glioma ............................................. 5 - Epe~dymoma IV -ventricle .................................. 3 * Therapy: Surgery: 37 (95%) - complete resection: 24 (66%) subtotal resection: 7 (18%) partial resection: 6 (16%) Radiotherapy: 17 (44%) Ftetd - Locat: t0 (5 BSG, 4 CA, l EPD) Craniospinal: 7 (6 MDB, ] EPD) Dosage - 2 5 - 3 5 Oy (gpine) 30-40 Gy (Cranium) 40-50 Oy (Posterior Fossa) Chemotherapy: 8 (20%) - MDB: 5 (VCR, MTX, CCNU/VCR~ MTX, PROC) - CA: ~ (VCR, PROC, C C N U ) - EPD: 1 (VCR, PROC, CCNU) - BSG: 1 (8 drugs in one day) -

-

-

2 Psychointellectual functioning A. Scholar/occupalional level Good .............................................. 2 Points - Fair ................................................. 1 Point - Poor ................................................ 0 Points B. Intelligence quotient (IQ) 90 ................................................ 3 Point5 - 7(~-g9 .............................................. 1 Feint < 70 ................................................ 0 Poinls C. Mental disorders No .................................................. 1 Point - Yes ................................................. 0 Points -

-

>

-

-

3~ Endocrine and growth evaluation -

Lever l ............................................ 3 Potat~ - Level 2 ............................................ 2 Petals Level 3 ............................................ 1 Point

-

Score: 1 + 2 + 3 = * Group A = 13 Points. Group B = 11, 12 Points. * G r o u p C = 8-10 Points. * G r o u p D = < 8 Point~.

-

-

-

-

-

CA: Cerebellar Astrocytoma. MDB: Medulloblastoma. BSG: Brain Stem Glioma. EPD: Ependymoma. CompLete Resection: 100% removal of tumor. 5~sbtotal Resection: 7 ~-99 % removal of tumor. Parlial Resection: < 75% removal of l u m o r VCR: Vincristine. MTX: Methotrexate. PROC: Procarbazine.

70 group of patients and c o m p a r e d with the remaining of patients except where i~dica~ed.

fled as having Level I (38%), 11 cases as Level II /28%), 8 cases as Level I I I (21%), and 5 cases as Level IV (13 %). Twenty-nine patients were practicing physical activities, 16 of t h e m without any difficulty.

Results Phase I

2. Psychointellectual evaluation Psycholointellectual sequelae were identified in 17 patients (44%). Scholar/occupational level was good in 22 cases (56 %), fair in 10 (26 %), and poor in the remaining 7 (18%). In 7 patients, mental disorders were detected: severe anxiety in 3, depression in 2, and social inadaptation in 2. Entertainment activities were p e r f o r m e d by 26 subjects (66,6%). I Q was determined in 33 patients: 9 of t h e m had an I Q between 70 and 90, and 4 m o r e had an I Q less than 70.

D a t a corresponding to the 39 subjects are shown in Table 3. The median age at diagnosis was 5 years (range 1-10y); the median age at evaluation was 14 years (R: 4-23y), with a median follow-up time of 9 years (R: 3-20y). There were 17 males and 22 females. Twenty-five children had cerebellar astrocyt o m a (CA), 6 had medulloblastoma (MDB), 5 had brain stem glioma (BSG), and 3 had e p e n d y m o m a of the forth ventricle ( E P D )

3, Growth and endocrine evaluation Ten patients developed endocrine and growth disorders: seven presented sequelae involving growth retardation, and three had precocious puberty (Table 4). In 9 of these patients, stimulation endocrine tests were completed: all cases had normal results. Four patients were included in endocrine level II and six in level III. In all seven patients with growth retardation, growth h o r m o n e levels were normal, and G H therapy was not used in any of these cases. T h e 4 cases with decreased upper/lower segment ratios had been treated with high-dose cranio-spinal irradiation. We detected three girls with precocious puberty. No thyroid dysfunction was noted.

Phase H 1. Neurologic and v&ual status Twenty-six patients (66,6%) had neurological and/ or visual impairment. Cerebellar dysfunctions were the most frequent (18 cases), manifested predominantly as intention t r e m o r and ataxia. The second most frequent dysfunctions were visual abnormalities, including oculomotor nerve palsies (13 cases). The remaining dysabilities were m o t o r deficits (7 cases), hearing losses (2 cases), and epilepsy (1 case). According to Bloom's scale, 15 cases were classi-

Table 4. Endocrine evaluation: patien{s with endocrine and/or growth sequelae Case

1

2

3

4

5

6

7

8

9

10

Diagnosis Tumor Age Dx Present age RT. CT. Surgery Level

SS CA 3 13 NO NO SUB 3

SS + U/L EPD 2 13 CSI YES PAR 3

SS BSG 2 4 LOC YES NO 3

U/L MDB 3 24 CSI YES PAR 2

U/L MDB 2 10 CSI YES PAR 2

U/L MDB 2 1i CSI YES PAR 2

B/C EPD 3 10 NO NO TOT 2

PP BSG 3 8 LOC NO PAR 3

PP MDB 4 tl CSI YES TOT 3

PP MDB 6 12 CSI NO TOT 3

Diagnosis: SS = Short Stature, U/L = Reduced Upper/Lower Segment Ratio, B/C = Retardation in Bone Age with respecl to Chronological Age. PP = PrecociousPuberty. CA = Cerebellar Astrocytoma. MDB = Medullo-blastoma,BSG = Brain Stem Glioma, EPD = Ependymoma. RT = Radiotherapy. CSI = Craniospinal Irradiation, LOC = Posterior Fossa Irradiation. CT = Chemotherapy.Surgery:TOT = Total resection, PAR = Partial resection. SUB = Subtotal resection. NO = No surgery. Level: Endocrine level.

71

Fig. 1. Children survivorsof posterior fossa tumors. Long-term sequelae. Correlation with age at presentation of tumor. Neural = neurologic sequelae. Psycho = pshychointellectualsequelae. Endoc = endoeri~ologieand growth sequelae.

Fig. 2. Children survivors of posterior fossa tumors. Long-term sequelae~ Correlation with type of surgery.Neurol = neurologic sequelae. Psycho = psychointellectualsequelae. Endocr = endocrinologicand gro'~th sequelae.

Phase III. Quality-of-life scores

nificant. Forty percent of patients with CA had neurological dysfunctions, but they were mostly minor complications: 76% of patients were classified in the groups I-II in Bloom's scale.

The 39 children survivors of P F T were classified as follows: * Group A: 7 patients (18%). * Group B: 12 patients (31%)_ * Group C: 8 patients (20%). * Group D: 12 patients (31%).

Influence of tumor type, age, sex, and treatment on quality of life

Type of tumor. Total number of sequelae were less frequent in patients witla CA with respect to the remaining children (p = 0.043), especially for endocrine and growth sequelae (p < 0.0001). Despite patients with CA had a lower number of all sequelae than patients with MDB, differences among these two groups were only significant for the visual and endocrine/growth dysfunctions (p = 0.013 and p = 0.0001 respectively). Q L scores were better in the CA group when compared to the MDB group (p = 0.018), but the difference was not significant when compared to the rest of tumors (p = 0.1), Patients with M D B had the highest number of sequelae (p = 0,02), the lowest Bloom's scores (p = 0.002), and the worst Q L scores (p = 0.02) with respect to the other groups. Patients with BSG and E P D had an intermediate number of sequelae and Q L scores, Neurolog~ca~ sequelae were frequent in a~l groups, especially in MDB; however, differences were not sig-

Age. Poor Q L were strongly related to young age. Children under 4 years of age at diagnosis had worse visual and endocrine functions than older patients (p = 0.03 and p = 0.0015): lower Q L scores were also noted in lhese young children (p = 0.02). Most of the visual dysfunctions were: impaired visual acuity and reduced visual field. Intellectual dysfunctions were also more frequent in children under 4 years, and they had less neurologic late effects; however, differences were not slatistica~y significant. If radiotherapy (RT) was employed in the young children, the consequences were devastating: 5 of 6 survivors were classified in group D (p < 0.0001) (Fig. 1). Sex. In our series, unfavorable outcomes were more frequent in female survivors than in males: 59% of girls vs. 41% of boys were in the C - D groups of QL. However, differences were not significant (p = 0.34). This results can be explained by the high number of aggressive tumors found in females and by the use of RT and CT in them. Surgery. Patients who had tumors which were totally resected had better outcomes than patients with non-Iotaily resected tumors, bul the differences were only significant for the endocrine and growth

72 Table 5. Long-term sequelae and quality of life in children survivors of posterior fossa tumors, Correlation with type of tumor

Tumor

CA (25)

MDB (6)

BSG (5)

EPD (3)

Neurologic seq. Visual seq. Psychointellect seq. Endocrine/growth seq. Bloom's scale: 1-11 Score QL: Group A Group B Group C Group D

10 (40%) 6 (24%) 8 (32%) 1 (4%)*** 19 5 10 5 5

5 (83%) 5 (83%)** 5 (83%) 5 (83%)*** 1"** 0 0 2* 4*

3 (60%) 2 (40%) 2 (40%) 2 (40%) 4 1 2 0 2

1 (33%) 0 2 (66%) 2 (66%) 2 1 0 1 1

CA = Cerebellar Astrocytoma. MDB = Medulloblastoma. BSG = Brain Stem Glioma. EPD = Ependymoma. SEQ = Sequelae. (*) p < 0.05. (**) p < 0.01. (***) p < 0.001.

anomalies (p = 0.015). This is very probably related to the additional therapy they received as compared with patients with totally resected tumors

(Fig. 2).

treated only with RT, 100% (8 of 8 patients) vs. 33% (3 of 9) were classified in groups C or D (p = 0.009). Sequelae were more frequent in the RT plus CT group (p = 0,086) when compared to the remainder of patients.

Radiotherapy (RT). Survivors who received radiation therapy had larger number of sequelae than patients not irradiated, especially visual and endocrinological sequelae (p = 0.03 and p = 0.0004 respectively). In the RT group, QL scores were very unfavourable in patients who were treated with high-dose cranio-spinal RT (100% in C-D groups) as compared to patients who received only local RT (p = 0.19) or to patients not irradiated (p = 0.0081) (Table VI).

Chemotherapy (CT). The use of CT was related to poor QL, although all patients who underwent CT were also treated with high-dose RT. When comparing patients treated with RT plus CT with those

Discussion It is estimated that by the year 2.000, one in every 1.000 adults reaching the age of 20 will be a longterm survivor of childhood cancer. The management of these survivors, and the evaluation of their quality of life (QL) have been receiving increased attention during recent years [3-5, 7]. We report here the evaluation of 39 pediatric survivors of PFT with a new scale for assessing QL. Astrocytomas of the cerebellum (CA) in children are mostly low-grade tumors, presenting a 10-year survival rate of nearly 90% /31-331. Complete re-

Table 6. Long-term sequelae and quality of life in children survivors of posterior fossa tumors. Correlation with radiotherapy

Type of sequelae

CSI (n = 7)

Local RT (n = 10)

No RT (n = 22)

Neurologic Visual Psychointellectual Endocrine/growth Score QL: Group A Group B Group C Group D

5 (71%) 5 (71%)* 5 (71%) 6 (86%)*** 0 0 2** 5**

4 (40%) 1 (10%)* 4 (40%) 2 (20%)*** 3 3 t 3

10 (45 %) 7 (32%)* 8 (36%) 2 (10%)*** 4 9 5** 4**

Local RT = Posterior Fossa Irradiation. CSI = Craniospinal Irradiation. No RT = No Radiotherapy. (*) p < 0.05. (**) p < 0.01. (***) p < 0.001.

73 section is often possible, but whether postoperative RT improves survival in subtotally excised tumors is still unclear [34]. Although half of our patients with CA had sequelaes, QL scores were high; these late effects were mainly minor neurological deficits that do not impair their normal lives. The incidence of other sequelae was low. These dysfunctions were directly related to the incomplete surgical resection and the subsequent use of RT. Recently reported series indicate a 5-year disease-free survival in childhood medulloblastoma (MDB) of 60-65 % following surgery and high-dose cranio-spinal irradiation (CSI) plus boost to the posterior fossa [35]. This rate can even improve with adjuvant CT [36, 37]. However, the QL in survivors is generally disastrous. Hope-Hirsch and cols. reported an incidence of neurologic, intellectual and emotional sequelae of 50, 58 and 47% at 5 years of treatment, worsening in all cases: no patient had normal employment at 10 years from diagnosis [38]. Other authors are not so pessimistic [3944]. Many studies have been designed to maintain the high survival rate and at the same time to reduce the severe sequelae derived mainly from CSI [4547]. In our series children with MDB were the most impaired group, with an uniformly poor QL and significant sequelae present in all of them. These findings were directly related to: the use of CSI, the use of CT and the age less than 4 years. tnfratentorial ependymomas (EPD) in childhood are rare, and their prognosis is considered to be poor even after surgical resection, RT and CT [48-52]. Two of the 3 patients with EPD had a bad QL: one was treated with surgery alone and the other was treated with surgery, CSI RT, and CT. The third EPD was treated only with surgery, and was included in group A. On the other hand, brain stem gliomas (BSG), despite often being low-grade tumors, have the same bad evolution, due to their inoperable location [33, 53, 54]. In our study, the BSG group of patients had moderate number of sequelae and intermediate QL scores: three were included in groups A-B, treated with surgery and/or local RT; and two in group D, treated with surgery, local RT, and CT. Our results can be compared to other series. Li and cols. reviewed 73 children survivors of PFT,

with a similar distribution of tumor types as ours [55]. They reported that 79% were in Bloom's levels I or II, presenting the same type of neurological sequelae. As suggested by others, perhaps the longer evolution of these patients (18 years) explains their better performance with respect to our series (66%) [5, 7, 32]. Kun and cols. [7] found 33% of patients with low IQ (< 80), and an incidence of emotional sequelae of 50%. In our serie, 39% of patients had IQ < 90, and only 18% developed emotional dysfunctions. Lannering and cols., in a study of 29 children with PFT with more than 5 years of evolution, noted a moderate to severe disability in 21%, and an IQ lower than 90 in 35%; these proportions rose twice in the group of irradiated patients [12]. We have also found this direct relation between the neurodevelopmental and psychointellectual status in our patients when RT was used. In our series, 26% of survivors had growth or endocrine disorders, an incidence that is variable in other reports. Most of patients were younger than 4 years, had MDB, the tumor was not completely resected, and were treated with RT. Height anomalies were the most frequent disturbances. In many studies, growth retardation is considered to be due to GH deficiency, which is secondary to hypothalamicpituitary irradiation. However, other factors that can influence final height are: the effect of RT on the growing spine, causing abnormal upper/lower segment ratios; early puberty, which accelerates the skeletal maturation; and hypothyroidism [4, 22, 42, 45]. In patients of short stature and low levels of GH, G H treatment is clearly indicated [23, 42]. In all of our patients with growth retardation, GH levels were normal. Four subjects who had been treated with CSI developed a decreased upper/lower segment ratio. Three girls had precocious puberty, and all of them had a normal final height. In spite of the published data, no thyroid dysfunction was detected by us. Several recent reports include the term 'Quality of Life' as the quantification of the performance status in childhood survivors of cancer [5, 10, 12, 13, 15, 16]. However, in most of these reports this concept is analyzed in a single way: (1) by studying only one type of tumor (p.e. medullobtastomas); (2) by evaluating individualized aspects of treatment (p.e.

74 radiotherapy); or (3) by quantifying specific dysfunctions (p.e. psycho-intellectual development, endocrine deficits). Furthermore, QL has been determined only by examining the neurological and psychointellectual status of the patient, overlooking in some cases the endocrine and developmental sequelae. The Karnofsky scale of performance status [20, 21] has been the most frequently employed measure of physical activity. It provides a quantification from 0 to 100 of the patients' disabilities, by rating their mobility, the degree of self-care, the employment capacity and life at home. Obviously, it is not readily applicable to children. The scale employed by us, established by Bloom [24], contains four categories of physical status, and is more easily applied to young children. Together with Bloom's scale, we have determinated the psychointellectual and endocrinological status of our patients, that way assessing QL of children survivors of posterior fossa tumors. The concordance of our results with those previously published does confirm the validity of this scale. We consider that our numerical scale can be applied to childen and adolescents who are long-term survivors of cranial tumors of all ages. Nineteen pediatric survivors of PFT (49%) had no or minimal sequelaes, performing well at school or at work, with a good QL. Eight more (20%) had moderate disability, with a QL that can be acceptable with an adequate rehabilitation. The remaining 12 subjects (31%) were classified as having a poor QL which can be improved slightly. These unfavourable outcomes were related to several factors: tumoTs other than astrocytoma of the cerebellum, especially meduliobtastoma, age iess than 4 at the time of diagnosis, incomplete tumoral resection, employment of RT (specially CSI) and CT. Currently, the great majority of our survivors are under specialized follow-up by the different sections of our hospital, including periodic neurological and visual examinations, physical rehabilitation programs, psychoemotional support and specialized education systems, as well as endocrine and developmental evaluations.

Acknowledgement We would like to acknowledge the contribution of Celia Ciscar, Pediatric Psychologist, for the psychointellectual evaluation of patients and Mike Harrison and Rita Sprudzs for their kind assistance in the preparation ol lhis manuscript.

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Address for offprints: V.C. Sanchez, Hospital Infantil La Fe, Unidad de Oncologia Pediatrica, Avda. Campanar, 21, 46009 Valencia, Spain