How much is too much? Folinic acid rescue dose in children with acute lymphoblastic leukaemia.

The effect of folinic acid rescue dose on the event-free survival of 71 children with acute lymphoblastic leukaemia was examined in a retrospective clinical study. All patients, diagnosed between 1 January 1980 and 1 January 1989, were treated according to the Norwegian Pilot protocol which included eight courses of high dose (6-8 g/m2/24 h intravenous infusion) methotrexate. Following the infusion, a uniform dose of 75 mg (at 36 h after the beginning of the drug infusion) and 15 mg (at 39-106 h) folinic acid rescue was administered to all patients, at predetermined intervals. The uniformity of the rescue dose resulted in distribution of dosages in the range of 38-140 mg/m2 and 7.5-28 mg/m2 for the different periods, respectively, when the dose was recalculated on the basis of the body surface area of the individual patients. The event-free survival of children receiving less or more than 15 mg/m2 (75 mg/m2) rescue dose was compared. Although no significant difference was found, a tendency was observed for a lower risk of relapse in patients receiving less folinic acid. No major methotrexate-related toxicity was observed in the group of patients receiving the lower dose of rescue. These observations suggest that the reduction of folinic acid rescue dose below the generally accepted 12-15 mg/m2 dose may increase the efficacy of high-dose methotrexate therapy while still remaining safe in preventing treatment-related toxicity. Prospective, randomised clinical trials are needed to examine the role of rescue as a determinant of effective exposure to methotrexate in patients receiving high-dose methotrexate treatment.

On the prognostic value of systemic methotrexate clearance in childhood acute lymphocytic leukemia.

The prognostic value of systemic methotrexate clearance (ClMTX) during high-dose therapy was evaluated in a cohort of 42 children with acute lymphocytic leukemia (ALL). As part of an extensive chemotherapy protocol, they had received a total of 293 methotrexate (MTX) infusions in the 6-8 g/m2 dose range. At the termination of the study, when they had all been followed up for 3.5 years or more, 26 of these patients were still in continuous complete remission, whereas 16 had suffered relapse. The intrapatient variability in ClMTX during the eight courses was up to six-fold. In 67% of the patients, the maximum level of ClMTX reached at least twice the minimum value. The coefficients of variation for the intra- and interindividual variability in ClMTX were 9-57% and 26-41%, respectively. The cumulative probability of relapse, estimated by the Kaplan-Meier procedure, was increased for patients with a high ClMTX during the initial treatment course, but the difference was not significant on a 5% level. There was no significant relationship between high individual median ClMTX and subsequent relapse of ALL. However, ClMTX during the initial infusion, the time-dependent mean for ClMTX, and the individual patient's median ClMTX, were significant predictors for event-free survival in a Cox proportional hazards regression analysis. The present study demonstrates gross pharmacokinetic variability and unpredictable values of ClMTX in subsequent courses after standardized administration of MTX to paediatric patients with ALL. In spite of the association between ClMTX and prognosis shown by some of the analyses, estimates of ClMTX rates may not necessarily be related to disease outcome in a way that can be exploited to the benefit of the individual patient.

Variability in methotrexate serum and cerebrospinal fluid pharmacokinetics in children with acute lymphocytic leukemia: relation to assay methodology and physiological variables.

Methotrexate (MTX) steady state concentrations were evaluated in 42 children who had received high-dose infusions (6-8 g/m2) for acute lymphocytic leukemia. Concentrations in serum and cerebrospinal fluid (CSF) measured by immunoassay were found to be highly variable. Reanalysis by a reference high-pressure liquid chromatography method ruled out analytical factors as a source of this variability. The correlation coefficient between the analytical methods was 0.77 for the serum data and 0.88 for the CSF data. The variability of serum and CSF concentrations was higher in younger patients (serum; P = 0.05 and CSF; P = 0.18), and the CSF concentration decreased with decreasing age and in later courses. Body surface area, body mass index, weight, and gender were not significantly related to MTX variability. We conclude that the pronounced pharmacokinetic variability seen during MTX infusions remains largely unexplained.

Methotrexate administered by 6-h and 24-h infusion: a pharmacokinetic comparison.

The pharmacokinetics of 8 g/m2 methotrexate (MTX) was compared following short (6 h) and long (24 h) infusions of the drug to 11 children with osteogenic sarcoma (OS; 42 infusion) and 28 children with acute lymphoblastic leukemia (ALL: 118 infusions), respectively. No difference was observed in the first-phase half-life, in systemic clearance or in the volume of distribution of the drug (P greater than 0.05). The concentration of MTX at the end of the infusion was approximately 4-fold higher when the drug was given over only 6 h. However, patients receiving 24-h infusions had approximately 9-fold higher levels by 24 h after the beginning of the infusion. The area under the data curve from start of the MTX infusion until the beginning of folinic acid rescue administration was significantly higher in patients with osteogenic sarcoma (6-h infusions), while the area under the log-data curve was significantly longer in the ALL group (24-h infusions) for the same period. The latter parameter is considered to be characteristic for the concentration-time-effect relationship. The longer duration of MTX administration (with delayed rescue) is thought to be more beneficial from the pharmacokinetic aspect. Patients with osteogenic sarcoma had significantly lower concentrations of MTX at the end of their last treatment with MTX than at the end of the first infusion. Patients developing MTX toxicity had shorter half-lives of MTX in the beta phase. It is suggested that cisplatin induced tubular loss of MTX and folinic acid is responsible for these observations. A wider application of clinical pharmacologic findings in the practice of the administration of cytostatics is indicated.

PharmCalc: program for the calculation of clinical pharmacokinetic parameters of methotrexate.

A new program package (PharmCalc) has been developed for the calculation of basic pharmacokinetic parameters (half-time, systemic clearance, renal clearance, AUC, volume of distribution, CSF/serum distribution ratio) of methotrexate (MTX). The program helps in the early recognition of patients at risk for toxicity and calculates the dosage of folinic acid rescue adjusted to the serum levels of MTX. The program offers a standardized and automated evaluation procedure for MTX pharmacokinetics and provides an easy-to-use tool for further research in this field. The concept and routines of the program are described.

7-Hydroxymethotrexate concentrations in serum and cerebrospinal fluid of children with acute lymphoblastic leukemia.

Concentrations of methotrexate (MTX) and 7-hydroxymethotrexate (7-OH-MTX) were determined by HPLC in the serum and cerebrospinal fluid (CSF) of 29 children with acute lymphoblastic leukemia. CSF and serum samples were obtained at the end of 104 infusions of MTX given in a dose range of 0.5-8.0 g/m2. Concentrations, distribution ratios in serum and CSF for MTX and 7-OH-MTX, and the metabolic index were analyzed with regard to the MTX dose, age and clinical state of the patients. A wide inter-patient (2- to 12-fold) but narrower (1.1- to 3.5-fold) intra-patient variability of the concentrations was observed. A dose-proportional increase in the metabolite concentration was found in serum. On the other hand, the elevation of the level of metabolite in CSF was less than proportional to the dose. The CSF/serum distribution data suggest the existence of a saturable carrier system for MTX and 7-OH-MTX between serum and CSF that has lower affinity for 7-OH-MTX. No correlation was found between concentrations of MTX and 7-OH-MTX in the serum of patients receiving the same dose of MTX. No significant difference was observed in the values for metabolic index between relapsed patients and those who were in continuous complete remission. A significant correlation was found between age and metabolic index: the younger the patient, the higher the metabolite concentration measured in serum.

Second malignant neoplasms after cancer in childhood or adolescence. Nordic Society of Paediatric Haematology and Oncology Association of the Nordic Cancer Registries.

OBJECTIVE: To assess the relative risk of developing a second malignant neoplasm in people with a diagnosis of cancer in childhood and adolescence. DESIGN: Register based follow up study. SETTING: Populations of Nordic countries. SUBJECTS: 30,880 people under the age of 20 with a first malignant neoplasm diagnosed during the period 1943-87. MAIN OUTCOME MEASURES: Relative and attributable risks of second malignant neoplasms by type of first cancer, age at first diagnosis, calendar period, sex, and country. Expected figures were based on the appropriate national incidence rates for cancer. RESULTS: 247 cases of second malignant neoplasms were observed in 238 patients, yielding a relative risk for cancer of 3.6 (95% confidence interval 3.1 to 4.1). The risk changed significantly from 2.6 in people first diagnosed during the 1940s and 1950s to 6.9 among cohort members included in the late 1970s and 1980s. Increases were observed for most types of cancer. Highest levels of the relative risk were seen during the 10 years immediately after first malignant diagnosis. The incidence of second malignant neoplasms attributable to the first cancer and associated treatments, however, showed a consistent rise throughout the 45 years of follow up. CONCLUSION: The estimated risks for a second malignant neoplasm were significantly lower than those found in most large hospital based studies but compatible with the results from a similar population based study in the United Kingdom. Extent of risk and cancer pattern were similar among the Nordic countries and are believed to be representative for a large part of the European population.

[Second cancer. Risk of a second malignant neoplasm in persons with cancer in childhood and adolescence]. / Sekundaer cancer. Risiko for sekundoer malign neoplasi hos personer med cancer i barne- og ungdomsår.

Cancer treatments in early life have in previous studies been associated in with high risks of developing a second malignant neoplasm. This study reports on the relative and attributable risks of second malignant neoplasms among 30,880 people under the age of 20, who had been identified in the files of any of the five Nordic cancer registers, 1943-1987. Overall, 247 cases of second malignant neoplasms were observed in 238 patients, yielding a relative risk for cancer of 3.6 (95% confidence interval 3.1-4.1). The risk changed significantly from 2.6 in people first diagnosed during the 1940s and 1950s to 6.9 among cohort members included in the late 1970s and 1980s. Highest levels of the relative risk were seen during the ten years immediately after first malignant diagnosis. The incidence of second malignant neoplasms attributable to the first cancer and associated treatments, however, showed a consistent rise throughout the 45 years of follow up. It was concluded that the estimated risks for second malignant neoplasms were significantly lower than those found in most large hospital based studies but compatible with the results from a similar population based study in the United Kingdom. Extent of risk and cancer pattern were similar among the Nordic countries and are believed to be representative for a large part of the European population.

Treatment of non-Hodgkin's lymphoma in childhood.

Non-Hodgkin's lymphoma (NHL) is a heterogenous group of disorders, and there exists no sharp border particularly between the T-cell lymphoblastic lymphoma and ALL in childhood. Major advance was made in therapy of pediatric NHL more than 16 years ago by Wollner (1974, 1979, 1982) with her introduction of the LSA2 S2 protocol. Disease-free-survival for all her first 58 patients was 70% for longer than 25 months at a median follow-up of 48 months. Relapse is rare after 2 years disease-freedom in NHL. The BFM group concluded in 1986 that approximately 70% of children with NHL can be cured. They introduced a new strategy for BCL and claimed that differential therapy must be used in NHL. Seventy-four of their 95 high risk BCL were in CCR after 3-4 years. T-cell lymphoma were treated as ALL. (Müller-Wehrich, 1986). Trials are going on with newer drugs and with high doses of both methotrexate and cytosine arabinoside. Anyhow, it seems to be a general consensus of opinion that high cure rate is due to aggressive multiagent chemotherapy while the role of radiotherapy is less clear in pediatric NHL. Heterogenicity of the group, lack of standardization in diagnostic work-up, inclusion of adults in some materials, exclusion of BCL in other, makes it difficult to compare the overall therapeutic results of different treatment protocols for pediatric NHL.(ABSTRACT TRUNCATED AT 250 WORDS)

Meningococcal disease--treatment of patients and household contacts below the age of 15 years.

Based on extensive experience and studies, some guidelines for the treatment of meningococcal disease are presented. The physician should be watchful for signs of meningococcal disease in its early phases and be ready to institute antibiotic and fluid therapy immediately. During transport of the patient to hospital, emergency medical treatment should be continued, and the hospital personnel should be alerted to receive the patient. At the hospital, a team of physicians should be ready to deal with the ventilatory, circulatory, fluid and electrolyte problems, and other complications of meningococcaemia, as well as to ensure administration of appropriate therapy. Antibiotic therapy for household contacts should be instituted as rapidly as possible. In this way it is hoped that the toll from this devastating infection in Norway may be lessened.

Childhood leukemia in Norway from 1963-1974 with special emphasis on own material.

Childhood leukemia in Norway in the period 1963-1974 with special emphasis on own material. Acta Paediatr Scand, 65:529, 1976. -A nation wide up-to-date survey of childhood leukemia in Norway including 499 cases in the period 1963-1974 is presented. The median survival for all cases was about one year. Around 20% of the 499 cases were still alive in Novemeber 1974. Twenty-five of the children were off therapy without any signs of relapse. In our own material thirteen of 42 cases of acute lymphatic leukemia (ALL) were still in primary remission after 3-9 1/2 years. Twelve of them were still off therapy and none had relapsed. Best results were achieved in the 31 cases of ALL followed closely by us all the time. The number of cases in continuous complete remission and the median survival rate in this series compares favourably with the last two studies published by the St. Jude group.

[Successful treatment of children with leukemia diagnosed 1966-72. A follow-up 23-29 years after diagnosis]. / Helbredelse av barn med leukemi diagnostisert 1966-72. En oppfølging 23-29 år etter diagnose.

Childhood leukemia was considered an incurable disease up to the beginning of the 1970. However, before 1976 we discontinued therapy in remission in 13 (30%) of 43 new cases of acute lymphocytic leukemia/acute undifferentiated leukemia diagnosed in the period June 1966-December 1972. One of the 13 cases relapsed after three years and the other after 14 years. Both were successfully retreated. One received intermediate dose metotrexate (0.5 g metotrexate/m2), the other high dose metotrexate (8 g metotrexate/m2) as consolidation. All 13 cases were healthy at the time of follow-up in the autumn of 1994. One testis had been removed in a case with initial testicular involvement and testicular relapse. No other definite late effects were diagnosed following treatment for childhood leukemia in the 13 cases. The article also contains information on health and socioeconomic status. The mean height of the six males was 183 cm, and of the seven females 170 cm. Nine of the 13 lived with a partner, one alone and three with parents.

Cessation of therapy in childhood leukemia. A survey of 160 cases from the Nordic Countries.

A survey is presented of 160 children from the Nordic countries who had their antileukemic therapy discontinued prior to November 1976. Twenty-seven of the 160 cases (17%) had suffered a relapse before May, 1977. Sixty-nine cases had their therapy stopped in the first ten months of 1976. All cases have been reported as acute lymphocytic leukemia. Different types of therapy schedules have been used. Thirty-five cases in sustained remission for more than 3 years without cessation of therapy are also included in the report, seventeen of whom had relapsed while still on therapy. Central nervous system or testicular relapse occurred in 21 of the total 44 cases who relapsed after three or more years of continuous remission, and whether they were on therapy or not.

Varicella in immunodepressed children.

Although dramatic improvements in the treatment of childhood malignancies have occurred during the last 20 years, infections occurring while they are on immunosuppressive chemotherapy now pose increasing problems for these patients. The literature on the subject and two personal illustrative fatal cases of varicella-zoster infections are reviewed pointing out the need for better prophylactic and antiviral therapy in this susceptible patient population.

High-dose methotrexate in childhood all.

An event-free survival is currently achieved in 70-80% of children diagnosed with acute lymphocytic leukemia (ALL). A decline in the long-term sequalae from therapy is a challenge at present. Due to the high incidence of central nervous system (CNS) relapse in ALL patients, cranial irradiation was introduced as a prophylactic measure in the beginning of the 1970s. Cranial irradiation, however, may cause secondary malignancies in the CNS. In recent years neurotoxicities have been demonstrated to follow cranial irradiation in a large proportion of ALL patients. Because of these deleterious effects, most ALL protocols are limited to the combination intrathecal and intravenous methotrexate as the standard for CNS prophylaxis. In the 1970s, an intermediate dose was administered, while from the 1980s a high dose of methotrexate was combined with intrathecal methotrexate. The regular methotrexate dose of later years has been in the range of 5-8 g/m2. The intravenous methotrexate dose has actually varied from 2 to 33.6 g/m2. The highest dose, 33.6 g/m2, has been without intrathecal instillation. In a study from Norway, high-dose methotrexate (6-8 g/m2) was used, and only two (2.2%) of 89 ALL cases showed CNS relapse, both of reversible kind. In the United Kingdom, a randomized controlled study was started in 1990. Results published so far are based on a segment of cases characterized by standard risk and white blood cell count below 50 x 10(9); a 4% reduction in CNS relapse was found for high-dose methotrexate in comparison to those treated only with long-term intrathecal methotrexate. The use of methotrexate unalterably warrants some precautions. Rescue therapy with folinic acid is usually started 36 h after initiating the methotrexate infusion. Steps are also taken to secure adequate intake of fluids and alkalinization of the urine. Provided irradiation is avoided, neurotoxicities rarely occur. For regular high-dose methotrexate adverse effects mostly involve mucositis and myelosuppresion.

Computed tomography in low-back-pain after femur-amputation for osteogenic sarcoma.

Following amputation of a lower extremity for osteogenic sarcoma, the lumbar muscles receive an asymmetric strain. This predisposes to low-back-pain. When this occurs, tumour-recurrence must be excluded. This report demonstrates the usefulness of high-resolution computed tomography (CT) in this clinical situation.

Systemic clearance of methotrexate in the prognosis of acute lymphoblastic leukemia in children.

The prognostic value of systemic clearance of methotrexate (MTX) has been evaluated in 58 children with acute lymphoblastic leukemia, receiving altogether 380 MTX infusions in a dose range of 0.5 to 33.6 g/m2. The linear regression analysis of dose-steady state concentration relationship revealed that relapsed children had significantly lower steady state concentration of MTX (faster systemic clearance) than those who remained in continuous complete remission (CCR), whatever dosage of the drug was given. Relapsed children (n = 25) had a systemic clearance of MTX 122.5 +/- 55.5 ml/minute/m2 versus 71.8 +/- 25.8 ml/minute/m2 found in the CCR patients (n = 33) when the dosage of MTX was 0.5 to 1.0 g/m2. When the dose was 6.0 to 8.0 g/m2 the clearance values were 93.27 +/- 32.6 versus 61.8 +/- 24.5 ml/minute/m2, respectively. The differences are statistically significant (P less than 0.001). In 16 of 25 relapsed patients (64%) an increase of the systemic clearance has been observed during the consecutive treatments, but only 4/33 CCR patients (12%) has expressed such a phenomenon. The dose-independent prognostic relevance of systemic clearance of MTX as a possible sign of resistance to MTX is concluded.

A comparative study on the pharmacokinetics of methotrexate in a dose range of 0.5 g to 33.6 g/m2 in children with acute lymphoblastic leukemia.

Concentrations of methotrexate have been determined in the serum and cerebrospinal fluid after 406 infusions of methotrexate to 58 children with acute lymphoblastic leukemia. The dose of methotrexate varied between 500 mg/m2 and 33,600 mg/m2. Pharmacokinetic analysis of the data has been carried out. The effect of dose, age, and number of treatments on steady-state concentration, serum half-life, cerebrospinal fluid (CSF) serum distribution ratio, volume of distribution, systemic clearance of methotrexate was examined. The elevation of dose resulted in a nonproportional increase of the steady-state concentrations both in serum and CSF. The great inpatient and interpatient variations of steady-state concentrations caused only statistically not significant differences in the parameters of different subgroups of dosages. Correlation was found between concentrations of methotrexate in serum and CSF. One to 4 years old children were found to have lower steady-state concentrations of methotrexate in the serum and CSF, greater volume of distribution and faster clearance of the drug. Dose-dependency and age-dependency of methotrexate pharmacokinetics has been concluded.