Basal metabolic rate in children with a solid tumour.

OBJECTIVE: To study the level of and changes in basal metabolic rate (BMR) in children with a solid tumour at diagnosis and during treatment in order to provide a more accurate estimate of energy requirements for nutritional support. DESIGN: An observational study. SETTING: Tertiary care at the Centre for Paediatric Oncology, University Hospital Nijmegen. SUBJECTS: Thirteen patients were recruited from a population of patients visiting the University Hospital Nijmegen for treatment. All patients asked to participate took part in and completed the study. INTERVENTION: BMR was measured by indirect calorimetry, under stringent, standardised conditions, for 20 min and on three different occasions in all patients. Continuous breath gas analysis using a mouthpiece was performed. Weight, height and skinfold measurements were performed before each measurement. MAIN OUTCOME MEASURES: BMR was expressed as percentage of the estimated reference value, according to the Schofield formulas based on age, weight and sex, and in kJ (kcal) per kg of fat-free mass. RESULTS: At diagnosis, the BMR was higher than the estimated reference BMR in all patients and 44% of the patients were considered hypermetabolic. Mean BMR (as percentage of reference) was significantly increased (11.6% (s.d. 6.7%); P=0.001), but decreased during treatment in 12 of the 13 patients (mean decrease 12.7% (s.d. 3.9%); P<0.0001). Furthermore, a significant negative correlation (P=-0.67; P=0.01) was found between the change in BMR and tumour response. CONCLUSIONS: These data suggest that the BMR of children with a solid tumour is increased at diagnosis and possibly during the first phase of oncologic treatment. This may be important when determining energy requirements for nutritional support.

Nasogastric tube feeding in children with cancer: the effect of two different formulas on weight, body composition, and serum protein concentrations.

BACKGROUND: Treatment of cancer cachexia partly involves the administration of adequate amounts of energy. The aim of this study was to assess the tolerance and efficacy of two equal volumes of tube feeding, one with a standard (1 kcal/mL) and one with a high energy density (1.5 kcal/mL), during the intensive phase of treatment. METHODS: Nutritional status was assessed weekly, in 27 children with a solid tumor, by measuring weight, height, midupper arm circumference, biceps and triceps skinfold, and serum proteins. Tolerance was assessed by recording the occurrence of vomiting and by expressing the administered volume as a percentage of the required volume. RESULTS: Both formulas were equally well tolerated, leading to a significantly higher energy intake in the energy-enriched formula group. In both formula groups, all anthropometric variables increased significantly (range of mean increase, 5.2% to 25.5%; p < .05) during the first 4 weeks of intervention. Between 4 and 10 weeks, variables continued to increase significantly in the energy-enriched group, resulting in adequate repletion, in contrast to the standard formula group. The concentration of serum proteins, low at initiation of tube feeding, returned to the normal range within 2 to 4 weeks with no significant differences between the two groups. CONCLUSIONS: The energy-enriched formula was more effective in improving the nutritional status of children with cancer during the intensive phase of treatment than the standard formula. Intensive, protocolized administration of an energy-enriched formula should therefore be initiated as soon as one of the criteria for initiation of tube feeding is met.

Association between the change in nutritional status in response to tube feeding and the occurrence of infections in children with a solid tumor.

In 32 children with a solid tumor, the association between the change in weight for height, in response to 4 weeks of tube feeding during the intensive phase of treatment, and the occurrence of leukopenia, leukopenic infections, and nonleukopenic infections in a period thereafter (4-10 weeks) was studied. Factors possibly influencing the change in weight for height during the first 4 weeks of tube feeding were also assessed. A statistically significant negative correlation (rho = -0.59; p < .001) was found between the change in z-score of weight for height in response to the first 4 weeks of tube feeding, and the occurrence of nonleukopenic infections between 4 and 10 weeks. A reduced occurrence of nonleukopenic infections resulted in a significant reduction of the number of days of infection-related hospital admission (rho = .45; p = .009), which, besides providing advantages for the patient, also had economical benefits. The change in weight for height in response to tube feeding was mainly influenced by the incidence of therapy-induced vomiting (r = -.45; p = .02) and by the amount of energy provided by tube feeding (r = .47; p = .007). Based on these findings, it is recommended that naso-gastric tube feeding be used in children with a solid tumor during the early intensive phase of treatment, and that one should aim for a considerable increase in weight for height during the first 4 weeks of administration, since this has been shown to reduce the number of nonleukopenic infections in a subsequent period. The increase in weight for height may be improved by providing an optimal antiemetic protocol, which will increase energy uptake, and an energy-enriched formula, which will increase energy intake.

Liposomal daunorubicin (DaunoXome) in children with recurrent or progressive brain tumors.

Liposomal daunorubicin (DaunoXome = DNX) has been used in 14 children with recurrent or progressive growing brain tumor. DNX was given as a 1-h intravenous infusion with a dose of 60 mg/m2, once every 4 weeks, up to a cumulative dose of 600 mg/m2. At 3-month intervals the tumor process was evaluated on MRI or CT scan. Tumor response and toxicity of DNX were recorded according to the WHO guidelines. In 6 of the children a response has been established: 2 had complete responses, of which one relapsed again after 3 months; in 3 children a partial response was found. Two children showed stable disease. In 6 children the tumors grew progressively. In all responding children a remarkable subjective response was found. The toxicity of DNX at this dose was mild with a mild bone marrow depression and a slight but certain cardiotoxicity in 3 children. For the whole group the left ventricular function decreased with 13.8%. In 1 child the DNX treatment was stopped because of a decrease of the shortening fraction to 20%. In 4 children some hair loss was observed at the end of the treatment. In 3 children mental depression occurred that was associated with the administration of DNX. DNX is a well-tolerated and effective drug in the treatment of slowly progressive or recurrent brain tumors in children.

Effects of naso-gastric tube feeding on the nutritional status of children with cancer.

OBJECTIVE: To study the effect of sufficient energy intake, by means of the protocolized administration of naso-gastric tube feeding, on the nutritional status of a child with cancer. DESIGN: A comparative experimental study. SETTING: Tertiary care at the Centre for Pediatric Oncology, South East Netherlands, University Hospital, Nijmegen. SUBJECTS: Seven children, newly diagnosed with cancer, were included in the experimental study and all completed the trial period. Fourteen patients were included in the retrospective study. They were randomly chosen from a group of patients previously treated for a malignancy at our department and who had received naso-gastric tube feeding for at least 16 weeks. INTERVENTION: Protocolized (experimental group) vs non-protocolized (retrospective group) administration of naso-gastric tube feeding over a period of 16 weeks. The main difference was the amount of tube feeding administered. In addition to energy from other foods, children in the experimental group received 106+/-13% of their total daily energy requirements (TDER) by means of tube feeding, whereas children in the retrospective group had received 75+/-24%. MAIN OUTCOME MEASURES: Weight as a percentage of weight for height according to the 50th percentile of a healthy reference population=ideal weight. RESULTS: Weight, expressed as a percentage of the ideal weight, increased significantly in the experimental group (18.2 8.4; P=0.01) and the retrospective study group (5.2 7.3; P=0.001). However, the increase was statistically significant in favour of the experimental group (P=0.003), in which all the children reached their ideal weight, compared to 21% in the retrospective group. CONCLUSION: Aggressive protocolized nutritional intervention during the intensive phase of anti-cancer treatment, in the form of naso-gastric tube feeding that provides the child's total daily energy requirements, results in considerable improvement in the nutritional status.

A lack of neuroblastoma in Down syndrome: a study from 11 European countries.

An epidemiological investigation in 11 European countries comprising a total childhood population of 54.1 million children and using 8 separate data sources was conducted to evaluate the occurrence of neuroblastoma in Down syndrome (DS). No cases of DS were detected among 6724 infants and children with neuroblastoma, although more than five were expected. This highly significant result (P = 0.0045 according to the Poisson test) is consistent with data in the literature, which contains only two poorly detailed cases in epidemiological studies and one ganglioneuroma in a DS mosaic patient. Like other tumors, such as leukemias, testicular germ cell tumors and lymphomas are in excess in DS patients; the lack of neuroblastomas does not reflect a general decreased incidence of cancer but rather a specific underrepresentation of this precise tumor. S-100 b protein, the gene for which maps to the long arm of chromosome 21, (a) is overproduced in DS patients, (b) produces growth inhibition and differentiation of neural cells in vitro, (c) is abundant in good-prognosis neuroblastomas, and (d) has been shown to induce growth inhibition and differentiation and cell death in several human and murine neuroblastoma cell lines and could be responsible for this variation. Additional epidemiological and experimental studies are warranted to confirm our interpretation of these data.

Chemotherapy with Adriamycin (doxorubicin) and CCNU (lomustine) in four children with recurrent craniopharyngioma.

BACKGROUND: The prognosis of craniopharyngioma in children after subtotal surgical removal, followed by irradiation of remaining tumour with 50 Gy, is better than usually reported. In our subjects we found a relapse rate of 5% in the last 20 years. The treatment of recurrences forms a special problem because the possibilities of adjuvant radiotherapy are restricted. We report on a chemotherapeutic treatment after multiple or very rapid recurrences of craniopharyngioma in four children. METHODS: Four children experienced their first tumour recurrence at respectively 3, 8, 50 and 59 months after the initial treatment. New neurosurgical attempts to remove the recurring tumour, and in one patient a second course of radiotherapy, were performed, but there were two or more recurrences in these children, resulting in further restriction of surgical or radiotherapeutical possibilities. Chemotherapy was given, consisting of five intravenous ambulatory courses of Adriamycin (doxorubicin) (33 mg/m2/day, continuously over 3 days) together with oral CCNU (lomustine) (80 mg/m2 at day 1) at 6-weeks intervals. RESULTS: After the chemotherapy there was no further tumour recurrence after 12, 10, 3 and 3 years respectively. In the third patient a cystic relapse occurred after 3 years' remission. In the fourth patient a complete regression was observed of the cystic part of the tumour. The side-effects of the chemotherapy consisted of alopecia and bone marrow depression. No signs of cardiomyopathy have been found. CONCLUSION: Treatment of recurrent craniopharyngioma in children by chemotherapy with anthracyclines and nitrourea-derivates may be effective.

Calcifications of the basal ganglia in children with brain tumours.

Calcifications in the basal ganglia have been found in nine (5.4%) of all children treated for any kind of brain tumour in our department. This has occurred over a mean period of 2.8 years after diagnosis. The group of patients has been compared with a group of other children, matched for age, sex, histologic diagnosis and tumour treatment, but without calcifications of the basal ganglia. The groups differ from each other with respect to a significantly higher incidence of hypothyroidism and growth hormone deficiency in the group of children with calcifications in the basal ganglia. Moreover the children with calcifications show a larger IQ-loss. Although the pathogenesis of the calcifications of the basal ganglia is not known, an association of damage to the vascular bed of the basal ganglia due to periods of increased intracranial pressure, together with endocrine deficiencies is discussed. We advise an adequate supplementation in cases of endocrine deficiencies in children treated for brain tumours as early as possible.

Shortened and diminished pubertal growth in boys and girls treated for acute lymphoblastic leukaemia.

Statural growth during puberty was studied longitudinally in 28 patients treated for acute lymphoblastic leukaemia. All patients received prophylactic cranial irradiation. The age at diagnosis was below 7 years, the age at final investigation was above 16 years for girls and above 18 years for boys. Growth was analysed using the Kernel estimation. In girls the onset of puberty and menarche was at a younger age, as compared to reference values, and the duration of the pubertal growth spurt was shorter. Compared to early maturing girls, the growth velocity at peak height velocity was lower. This resulted in a final height which was shorter than expected on the basis of the height standard deviation score before the start of puberty. In boys the duration of the pubertal growth spurt was shorter and the height gain during the growth spurt less than in the reference population. In both sexes the bone age development was accelerated.

Influence of treatment modalities on body weight in acute lymphoblastic leukemia.

Weight for height of 92 patients (51 girls and 41 boys) treated for acute lymphoblastic leukemia (ALL) was evaluated in a longitudinal study. Fifty-four patients received cranial irradiation (CI) with a dose of 18 or 24 Gy and 38 patients did not receive CI. Seventy-seven patients were treated according to a normal-risk protocol and 15 patients received more intensive chemotherapy according to a high-risk protocol. In most of the patients the duration of follow-up was 12 years for irradiated patients and 4.5 years for the nonirradiated patients. Thirty of 92 patients were treated according to a protocol without CI, but with a difference in the use of corticosteroids: 19 patients received dexamethasone during the remission-induction and maintenance treatment and 11 patients received prednisone. The influence of dexamethasone vs. prednisone, sex, CI and high-dose vs. low-dose chemotherapy on weight for height was evaluated. Patients who received dexamethasone showed a significant increase in weight for height immediately after the start of therapy. In patients who received CI, weight for height significantly increased after the first year of treatment. The overweight in these patients persisted during the whole follow-up period. The weight for height of patients treated with prednisone and of patients who did not receive CI was below the mean of the normal population during treatment but was not different from normal after cessation of therapy. No difference in weight gain was seen between boys and girls and between patients who were treated with high vs. normal-risk protocols.

Ondansetron in radiation therapy of brain tumor in children.

Ten children receiving 5 to 6 week courses of radiotherapy after brain tumor surgery were given ondansetron treatment for persistent nausea and emesis. All patients continued the ondansetron treatment until the end of their radiotherapy course. Nausea, emesis, appetite, and adverse events were scored throughout the ondansetron treatment period. Ondansetron was well tolerated by all patients and was effective at reducing symptoms in 60% of the children.

Chemotherapy plays a major role in the inhibition of catch-up growth during maintenance therapy for childhood acute lymphoblastic leukemia.

OBJECTIVE: In children treated for acute lymphoblastic leukemia (ALL), catch-up growth occurs after cessation of therapy and not during maintenance therapy. In this study we investigated whether this inhibition of catch-up growth during maintenance treatment is attributable to the influence of chemotherapy or to the influence of corticosteroids. PATIENTS: Forty-six children treated for ALL were included in the study. In 27 patients maintenance therapy comprised vincristine (VCR), prednisone (Pred), or dexamethasone (Dexa) alternated with 6-mercaptopurine (6-MP) and methotrexate (MTX) and 19 patients received maintenance therapy with 6-MP and MTX only. Treatment did not include cranial irradiation. RESULTS: Statural growth during maintenance treatment was comparable in both groups over the study period of 1.5 years. CONCLUSION: Chemotherapy with 6-MP and MTX, and not corticosteroids, is the main factor that prevents catch-up growth from occurring during maintenance therapy for ALL.

Influence of treatment modalities on prepubertal growth in children with acute lymphoblastic leukemia.

The statural growth of 85 prepubertal children treated for acute lymphoblastic leukemia was evaluated in a longitudinal study over 4.5 years. Patients were divided into three groups according to central nervous system prophylaxis: 37 patients received cranial irradiation with a dose of 24 Gy, 15 received a dose of 18 Gy, and 33 were not irradiated. According to the risk of leukemia, patients were divided into normal-risk (n = 74) and high-risk (n = 11) groups. The duration of treatment was 2 years, during which all patients showed growth retardation. The relative standard deviation score for height declined from 0 to -0.7 for the irradiated patients and from 0 to -0.2 for the non-irradiated group (P = 0.0001). There was no difference in growth pattern between cranial irradiation with 18 versus 24 Gy and chemotherapeutic treatment according to high-risk versus normal-risk protocols. However, a negative synergistic effect of more intensive chemotherapy and cranial irradiation on growth was demonstrated.

Astrocytoma in childhood: survival and performance.

Seventy-nine children (35 female, 44 male) with proven or presumed astrocytoma were treated from 1967 to 1987. The tumors were supratentorial located in 24 children, cerebellar in 21 children, and pontine in 34 children. If possible, a radical tumor resection (4%), a subtotal tumor resection (51%), or a biopsy (8%) was performed. The predominant pathological Kernohan grading for the supratentorial, cerebellar, and pontine located tumors were grades II, II, and IV respectively. Histology was unknown in 15 out of 34 pontine tumors and in 1 out of 24 supratentorial tumors. Low-graded tumors (46%) were irradiated with a local field (1.8/45-50 Gy) and children with high-graded tumors (34%) received a total brain irradiation (1.8/40 Gy) followed by a boost irradiation (10 Gy) in 5 or 6 fractions. Overall 1-, 5-, and 10-year survivals of children with supratentorial, cerebellar, and pontine located tumors were 96%-91%-46%, 95%-95%-95%, and 35%-20%-20% respectively. For all tumor locations, 77% of deaths occurred within 2 years of treatment. The performance status of both children with supratentorial and cerebellar astrocytoma showed an increase during the first year of treatment and then stabilized on a rather high level (mean performance after 5 years of 60% and 70% respectively). Children with pontine tumors showed a steep decrease in performance status during the first year of treatment and then stabilized on a low level (mean performance after 5 years of 15%). In our study, children with supratentorial astrocytoma showed improvement in both survival and performance status after irradiation following surgical removal of the tumor.(ABSTRACT TRUNCATED AT 250 WORDS)

[Biochemical and clinico-pharmacological aspects of antimetabolites in the treatment of leukemia]. / Biochemisch- en klinisch-farmacologische aspecten van antimetabolieten bij de behandeling van leukemie.

Methotrexate (MTX) and 6-mercaptopurine (6MP) have been used since 30 years in the maintenance treatment of acute lymphoblastic leukemia (ALL) of childhood. A synergistic effect of this combination was demonstrated in mouse and childhood leukemia. In this article an overview is given of our investigations, concerning the biochemical basis of this synergism. This synergism is caused by a selective inhibition of the purine de novo synthesis in malignant lymphoblasts by MTX, associated with an enhanced intracellular uptake of 6MP. Pharmacokinetic studies of MTX in various schemes of prophylactic central nervous system treatment in ALL are discussed. Treatment with 24-hr infusions of MTX in a dosage of 5 g/m2, as recommended in the new BFM-86/SNWLK ALL VII protocol, seems to be optimal. Pharmacokinetic studies of intravenous 6MP infusions demonstrated a good cerebral fluid penetration. Exploiting the synergistic action of the combination of MTX and 6MP may offer an improvement of the prophylactic central nervous systems treatment in ALL in the future, using intravenous administration of both MTX and 6MP.

Methotrexate concentration levels in the cerebrospinal fluid during high-dose methotrexate infusions: an unreliable prediction.

In 25 children with lymphoid malignancies, 96 high-dose methotrexate infusions (3 g/m2) with a duration of 24 h have been administered as a part of the treatment schedule. A lumbar puncture was performed to apply methotrexate intrathecally. The moment of lumbar puncture during the infusion was chosen at different times. In 76 of the infusions the concentration of methotrexate in the cerebrospinal fluid and in plasma were determined just prior to the intrathecal administration. From the second to the eighth hour after the initiation of the infusion the concentration of methotrexate in the cerebrospinal fluid and in plasma were determined just prior to the intrathecal administration. From the second to the eighth hour after the initiation of the infusion the concentration of methotrexate in the cerebrospinal fluid appeared to be significantly lower than 16 or 24 h after the initiation of the infusion. Of all samples during the infusions, the plasma concentration varied a tenfold (2-20 X 10(-5) mol/L), but the cerebrospinal fluid concentration of methotrexate varied about a 300-fold (3.5-900 x 10(-8) mol/L). No correlation could be found between the plasma concentration of methotrexate and the cerebrospinal fluid concentration. It is concluded that the methotrexate concentration in the cerebrospinal fluid cannot be predicted by determining the plasma concentration. It takes at least 8 h of infusion before a steady-state concentration of methotrexate is reached in the cerebrospinal fluid. In high-dose methotrexate infusions without intrathecal therapy, the dose of 3 g/m2 is the minimum amount of methotrexate to reach the minimum therapeutic concentration 5 x 10(-7) mol/L) in the cerebrospinal fluid for the treatment of subclinical central nervous system invasion of malignant lymphoid cells. To maintain the minimum therapeutic concentration according to the CxT principle the duration of the infusion should be preferably longer than 24 h.

Tolerance of 24-hour infusions or low- and high-dose bolus injections of adriamycin in children.

In 75 children with mainly lymphoid malignancies, adriamycin was used as part of the treatment. Three groups were distinguished: group I (n = 18), with an adriamycin dose of 30 mg/m2 as bolus; group II (n = 30), with a dose of 100 mg/m2 divided over 2 subsequent days; and group III (n = 27), with a dose of adriamycin of 100 mg/m2 given as a 24-h infusion. The tolerance of the low dose was the best. In group III small differences in the tolerance were observed. The recovery of the white blood cell count showed a delay in the infusion group, whereas the bolus injection group showed more vomiting. Severe vascular lesions occurred in the infusion group. The use of 24-h infusions of adriamycin is feasible when central venous accesses or totally subcutaneous intravenous devices are used. According to the literature, when long-term invasions of adriamycin are used, the risk of cardiomyopathy is diminished, without influencing the antitumor activity of adriamycin.