Central nervous system EBV lymphoproliferative disorder in a patient with rhabdomyosarcoma

Epstein–Barr virus associated lymphoproliferative disorder (EBV‐LPD) occurs in patients with immunodeficiency, but it has not been well described in patients who have received chemotherapy for solid tumors. We describe a child with rhabdomyosarcoma who developed isolated central nervous system (CNS) EBV‐LPD during combination chemotherapy with vincristine, actinomycin D and cyclophosphamide. The patient was treated with high‐dose methotrexate (HD‐MTX) for CNS EBV‐LPD and then treated with rituximab in addition to HD‐MTX because of the emergence of LPD in the liver. I.v. rituximab combined with HD‐MTX might be effective therapy for CNS EBV‐LPD.     

Methotrexate‐associated alterations of the folate and methyl‐transfer pathway in the CSF of ALL patients with and without symptoms of neurotoxicity

Background

Severe neurotoxicity has been observed after systemic high‐dose and intrathecal methotrexate (MTX) treatment. The role of biochemical MTX‐induced alterations of the folate and methyl‐transfer pathway in the development of neurotoxic symptoms is not yet fully elucidated.

Procedure

MTX, 5‐methyltetrahydrofolate, calcium folinate, S‐adenosylmethionine, and S‐adenosylhomocysteine were measured in the cerebrospinal fluid (CSF) of 29 patients with acute lymphoblastic leukemia (ALL) who were treated with high‐dose MTX (5 g/m²) followed by calcium folinate rescue (3 × 15 mg/m²) and/or intrathecal (8–12 mg) MTX. Two patients developed subacute MTX‐associated neurotoxicity. CSF was obtained by lumbal puncture 1–3 weeks after administration of MTX and shortly after the occurrence of neurotoxicity. The analytes were measured using HPLC assays with UV and/or fluorescence detection.

Results

In non‐toxic patients, CSF concentrations of 5‐methyltetrahydrofolate and S‐adenosylmethionine were in the normal range 2 weeks after administration of high‐dose and intrathecal MTX followed by rescue. In contrast, when these patients received intrathecal MTX without rescue, 5‐methyltetrahydrofolate concentrations were significantly decreased 12 days after the first MTX administration. S‐adenosylmethionine concentrations were significantly decreased up to 45 days. The two patients suffering from neurotoxicity had decreased levels of 5‐methyltetrahydrofolate and S‐adenosylmethionine during or following toxicity. S‐adenosylhomocysteine was determined in all samples of neurotoxic patients but was below the limit of quantification in most samples of non‐toxic patients. Calcium folinate was not detected; MTX was present only in samples obtained during its infusion.

Conclusion

Intrathecal MTX without folinate rescue as well as MTX‐associated neurotoxicity are likely to be associated with specific alterations of the folate and methyl‐transfer pathway. Pediatr Blood Cancer 2009;52:26–32. © 2008 Wiley‐Liss, Inc.     

Serum Creatinine Versus Plasma Methotrexate Levels to Predict Toxicities in Children Receiving High-dose Methotrexate

Facilities for measuring methotrexate (MTX) levels are not available everywhere, potentially limiting administration of high-dose methotrexate (HDMTX). We hypothesized that serum creatinine alteration after HDMTX administration predicts MTX clearance. Overall, 122 cycles in 50 patients of non-Hodgkin lymphoma or acute lymphoblastic leukemia aged ≤18 years receiving HDMTX were enrolled prospectively. Plasma MTX levels were measured at 12, 24, 36, 48, 60, and 72 hours; serum creatinine was measured at baseline, 24, 48, and 72 hours. Correlation of plasma MTX levels with creatinine levels and changes in creatinine from baseline (Δ creatinine) were evaluated. Plasma MTX levels at 72 hours showed positive correlation with serum creatinine at 48 hours (P = .011) and 72 hours (P = .013) as also Δ creatinine at 48 hours (P = .042) and 72 hours (P = .045). However, cut-off value of either creatinine or Δ creatinine could not be established to reliably predict delayed MTX clearance. Greater than 50% Δ creatinine at 48 and 72 hours significantly predicted grade 3/4 leucopenia (P = .036 and P = .001, respectively) and thrombocytopenia (P = .012 and P = .009, respectively) but not mucositis (P = .827 and P = .910, respectively). Delayed MTX elimination did not predict any grade 3/4 toxicity. In spite of demonstration of significant correlation between serum creatinine and Δ creatinine with plasma MTX levels at 72 hours, cut-off value of either variable to predict MTX delay could not be established. Thus, either of these cannot be used as a surrogate for plasma MTX estimation. Interestingly, Δ creatinine effectively predicted hematological toxicities, which were not predicted by delayed MTX clearance.     

Degradation and clearance of methotrexate in children with osteosarcoma receiving high-dose infusion

Plasma methotrexate (MTX) concentrations were quantitated in 34 patients after 127 high-dose (35–350 mg/kg) infusions with citrovorum factor rescue. Significant linear correlations have been obtained between methotrexate dosage and concentrations in plasma at 6 and 24 hours after the initiation of the therapy. However, similar trends have not been observed when 48- and 72-hour samples were analyzed. Clinical toxicity was not serious when the methotrexate level in plasma was < 4.5 × 10^?6 M at 48 hours after the start of a six-hour infusion in children. A minimal four-hour steady-state methotrexate plasma level can be maintained during a six-hour infusion. Children excrete methotrexate at a faster rate than adults; the half-life of MTX during the first phase of plasma clearance curve is one hour shorter in children. Urinary analyses have indicated that substantial methotrexate is metabolized. The chemical nature of these components has not been identified. Further, the urinary metabolic profiles varied among patients.     

Safety assessment of intensive induction therapy in childhood anaplastic large cell lymphoma: report of the ALCL99 randomised trial

Background

ALCL99 protocol including six courses of chemotherapy derived from the NHL‐BFM protocol is widely used for the treatment of paediatric anaplastic large‐cell lymphoma. In the ALCL99 trial, patients were randomised to receive MTX 1 g/m² in 24 hr with intrathecal injection (MTX1) versus MTX 3 g/m² in 3 hr without intrathecal (MTX3); then to receive or not vinblastine (high‐risk patients). The present study provides information about the acute adverse reactions (ARs) during the six courses of the ALCL99 treatment, assesses risk factors for ARs and evaluates the risk of overweight related to treatment.

Methods

Data concerning ARs were assessed using CTCv2 and analysed overall and according to the type of course.

Results

Between 1999 and 2005, 352 patients were recruited. Toxicity assessed after 2050 courses included grade 4 neutropaenia (70% of courses), grade 3–4 stomatitis (13%), grade 3–4 transaminase elevation (10%) and grade 3–4 infection (5%). Four patients (1%) died of toxicity. The toxicity profile differed between courses‐A (significantly more haematological toxicity) and courses‐B (significantly more stomatitis). The percentage of ARs was higher after the first course than after subsequent courses. Severe toxicity was more frequent after MTX1 than after MTX3 courses but did not differ between courses with or without vinblastine. Overall 20% of patients had a weight gain exceeding 20%.

Conclusions

The high rate of acute toxicity should be considered when using the ALCL99 protocol. Chemotherapy including MTX 3 g/m² in 3 hr was less toxic than the same regimen with MTX 1 g/m² in 24 hr. Adding vinblastine did not increase the risk of toxicity. Pediatr Blood Cancer 2011;56:1071–1077. © 2011 Wiley‐Liss, Inc.     

High-dose methotrexate therapy of childhood acute lymphoblastic leukemia: lack of relation between serum methotrexate concentration and creatinine clearance.

BACKGROUND: The objectives of this study were: (1) to analyze the relation of serum methotrexate (MTX) concentration with creatinine clearance, (2) to compare the leucovorin rescue dose administered to the patients based on creatinine clearance, with the one calculated according to serum MTX levels, and (3) to determine MTX-related toxicity. PROCEDURE: Thirty children with high-risk non-B acute lymphoblastic leukemia (ALL) treated according to the national protocol (PINDA 92) based on ALL BFM 90, were randomized to receive consolidation with four doses of either 1 or 2 g/m(2) MTX as a 24-hr infusion, at 2-week intervals (group M1 and M2, respectively). Serum MTX concentrations were measured at 24, 42, and 48 hr after beginning the infusion and were analyzed retrospectively. The creatinine clearance was calculated after 12-hr intravenous hydration prior to each MTX dose. Leucovorin dosage was adjusted according to creatinine clearance. RESULTS: Serum MTX concentrations at 24, 42, and 48 hr after starting the infusion were not related to creatinine clearance in both treatment groups. Leucovorin rescue administered according to creatinine clearance was excessive in 43% in group M1 and in 51% in group M2, as compared to the dose calculated according to serum MTX levels. No serious clinical complications were observed. CONCLUSIONS: These results suggest that creatinine clearance is not a good parameter to calculate leucovorin rescue. MTX-related toxicity in this group of patients receiving a dose of 1 or 2 g/m(2) and rescued with leucovorin without monitoring serum MTX levels was acceptable.     

Sequential chemotherapy of advanced colorectal cancer with standard or high-dose methotrexate followed by 5-fluorouracil

Thirty patients with advanced measurable colorectal cancer were randomized to receive either methotrexate (MTX) 200 mg/m² or 40 mg/m², followed in four hours by 5-fluorouracil (5-FU) 600 mg/m². Patients receiving the higher dose MTX were given leucovorin rescue 24 hours later. Eight of 13 patients treated with 200 mg/m² MTX + 5-FU developed severe hematologic toxicity, leading to two toxic deaths. In addition, 9/13 developed mild azotemia, and three patients had severe gastrointestinal toxicity. No patients with prior chemotherapy responded to either regimen. Among those without prior chemotherapy, there were two of six and three of eight partial responses, respectively, in the 200 mg/m² and 40 mg/m² MTX regimens. Sequential 200 mg/m² MTX followed by 5-FU after four hours has unacceptable toxicity. Sequential treatment with standard dose MTX + 5-FU is tolerable and merits further study.     

Prognostic significance of chemotherapy dosage characteristics in children with osteogenic sarcoma

High-dose methotrexate (HDMTX), adriamycin (ADR), and cisplatinum (CDDP) are effective agents in the treatment of osteogenic sarcoma (OS). Individual patient doses are determined by prior successful clinical trials but may be reduced due to ongoing toxicities. It is unknown whether individualized dose reductions of these drugs influence disease outcome. We retrospectively studied 27 consecutively enrolled children treated with HDMTX, ADR, and CDDP as adjuvant chemotherapy for OS, for correlations between disease outcome and several characteristics of drug, dosing: the cumulative MTX, CDDP, and ADR doses administered and the mean MTX blood levels for each patient. With a median follow-up of 59 months, the actuarial overall and disease-free survival rates were 70% and 59%, respectively. Factors which favorably influenced prognosis on univariate analysis were a cumulative ADR dose of >300 mg/m² (P = 0.0002) and a cumulative MTX dose > 114 gm/m² (P = 0.0048). By multivariate analysis only the cumulative ADR dose >300 mg/m² retained prognostic value. We conclude that adjuvant chemotherapy dosages may need to be adjusted for therapeutic efficacy in addition to adjustments made for toxicity. The effect of different cumulative HDMTX and ADR dosages on prognosis in osteosarcoma patients needs to be evaluated in a prospective trial. Med. Pediatr. Oncol. 28:179–182 © 1997 Wiley-Liss, Inc.     

Interaction between trimethoprim-sulfamethoxazole and methotrexate in children with leukemia

Because trimethoprim-sulfamethoxazole (TMP-SMX) causes neutropenia in children with leukemia, we investigated the possibility that pharmacokinetic interaction between methotrexate (MTX) and TMP-SMX causes accumulation of the antileukemia agent. We studied the pharmacokinetics of MTX given intravenously or orally to nine children with acute lymphoblastic leukemia, once with and once without TMP-SMX. There was an increase in free MTX fraction during TMP-SMX therapy in all patients, from (mean +/- SD) 37.4 +/- 11% without TMP-SMX to 52.2 +/- 6.4% with TMP-SMX (p less than 0.01). Plasma clearance of total MTX did not change significantly, whereas clearance of free MTX decreased significantly (from 12.5 +/- 4 to 7.6 +/- 1.5 ml/kg/min; p less than 0.05). There was a consistent decrease in the renal clearance of free MTX (from 12.1 +/- 6.8 to 5.6 +/- 2.4 ml/kg/min; p less than 0.05). Elimination half-life of MTX was not affected significantly by TMP-SMX. There was a significant correlation between serum concentrations of TMP-SMX and the percentage of decrease in the renal clearance of free MTX (r = 0.91; p less than 0.05). These changes in protein binding and tubular clearance of MTX, caused by competition with TMP-SMX, result in a mean 66% increase in systemic exposure to MTX and may explain the myelotoxicity often observed with the coadministration of the two drugs.     

Delayed methotrexate clearance in patients with acute lymphoblastic leukemia concurrently receiving dasatinib

We aimed to determine whether patients receiving dasatinib or imatinib concurrently with high‐dose methotrexate (HDMTX) had slower methotrexate clearance than patients not receiving a tyrosine kinase inhibitor (TKI) during the HDMTX infusion. Patients concurrently receiving dasatinib and HDMTX (N = 7) had significantly slower MTX clearance (P = 0.008) than patients not receiving a TKI (N = 111). Two patients receiving a TKI during a HDMTX infusion required glucarpidase. In vitro studies showed that dasatinib significantly inhibited methotrexate uptake by SLCO1B1‐expressing cells (P = 0.009). There may be an interaction between dasatinib and HDMTX, mediated by the transporter SLCO1B1, that causes a delay in MTX clearance.     

Pharmacokinetics of HD-MTX in infants,children, and adolescents with non-B acute lymphoblastic leukemia

A retrospective pharmacokinetic analysis was done of methotrexate serum levels after high-dose treatment (HD-MTX, four cycles at two-week intervals of 5 g/sq.¹m. over 24 h i.v.) in children with non-B acute lymphoblastic leukemia (ALL) with the specific aim of seeking differences in patients of different ages, including infants under one year. A total of 122 children (seven infants aged 3 months-1 year, 26 children aged 1–3 years, 68 children aged 3–10 years and 21 adolescents aged 10–15 years) with normal liver and renal function, receiving consolidation therapy at the Pediatric Clinic of Monza between May 1988 and April 1992, were enrolled in this study. MTX was given as an intravenous infusion in 24 h and serum concentrations were measured up to at least 72 h after the start of infusion by an enzyme immunoassay (TDX Abbot, Dallas, TX) in order to modulate folinic acid rescue. Pharmacokinetic analysis of MTX levels according to a two-compartment open model indicated that, compared to all children up to 10 years old, in adolescents older than 10 years the drug reached higher concentrations in serum and was cleared at a lower rate. Steady-state levels and AUC were from 60% higher to more than double and the total clearance of the compound, expressed either per square meter surface area or per kg body weight, in each cycle was significantly lower in adolescents >10 years of age, sometimes being only one-third of the clearance in infants (0.2 vs. 0.6 1/h/kg and 6.6 vs. 10.7 1/h/sq.m). The relationship between each age and systemic clearance was highly significant as measured by regression analysis. Methotrexate systemic clearance progressively decreased as a function of age. Subsequent treatments did not induce changes in MTX pharmacokinetics. These data suggest that the better tolerance of HD-MTX in children may have a pharmacokinetic basis. The faster elimination of MTX in infants, who usually show the worst prognosis, suggests that full doses could be safely used in order to maximize the antileukemic effect without a high risk of toxicity. © 1995 Wiley-Liss, Inc.     

Degradation and clearance of methotrexate in children with osteosarcoma receiving high-dose infusion.

Plasma methotrexate (MTX) concentrations were quantitated in 34 patients after 127 high-dose (35--350 mg/kg) infusions with citrovorum factor rescue. Significant linear correlations have been obtained between methotrexate dosage and concentrations in plasma at 6 and 24 hours after the initiation of the therapy. However, similar trends have not been observed when 48- and 72-hour samples were analyzed. Clinical toxicity was not serious when the methotrexate level in plasma was less than 4.5 X 10(-6) M at 48 hours after the start of a six-hour infusion in children. A minimal four-hour steady-state methotrexate plasma level can be maintained during a six-hour infusion. Children excrete methotrexate at a faster rate than adults; the half-life of MTX during the first phase of plasma clearance curve is one hour shorter in children. Urinary analyses have indicated that substantial methotrexate is metabolized. The chemical nature of these components has not been identified. Further, the urinary metabolic profiles varied among patients.     

Pharmacokinetic interaction between methotrexate and chloral hydrate

We report the case of a drug interaction between methotrexate (MTX) and chloral hydrate (CH) observed in a child treated for acute leukemia. Significantly slower MTX clearance and increased MTX exposure occurred on the first three courses of a high‐dose chemotherapy when co‐administered with CH despite normal renal function, adequate hydration, and alkalinization. Mean MTX area under the curve associated with CH administration was 1,134 µmol hours/L, compared to 608 µmol hours/L after discontinuation of CH. This interaction possibly resulted from a competition between anionic CH metabolites and MTX for renal tubular excretion. Pediatr Blood Cancer 2013; 60: 518–520. © 2012 Wiley Periodicals, Inc.     

Ifosfamide tolerance in osteosarcoma patients previously treated with cis-Diamminedichloroplatinum-II: Renal,hematologic, and neurologic observations

We attempted to ascertain renal, hematologic, and neurologic tolerance to ifosfamide (IFX) in pediatric patients previously treated with large single and cumulative doses of cis-Diamminedichloroplatinum-II (CDP) for osteosarcoma (OS). Twenty OS patients were treated with CDP: initially 150 mg/m² was administered every 2 weeks for a maximum of seven courses. Later, other agents, including additional CDP, were also administered. Twelve patients were treated with intra-arterial CDP, one with intra-arterial, and later intravenous CDP, and seven with intravenous CDP. Patients who relapsed were treated with IFX. Renal function was monitored by measuring creatinine clearance, serum electrolytes, total protein, albumin and CO₂ content, and urine analysis during IFX therapy. Prior to initiation of IFX, creatinine clearance was above 60 ml/min/m² in all except one patient who had developed a hemolytic uremic syndrome (HUS). Cumulative CDP doses ranged from 300 to 22,500 mg/m², and cumulative IFX doses 12 to 128 gm/m². Myelossupression was monitored by obtaining routine hemograms midway between each course of treatment. Neurologic tolerance was assessed by reviewing the medical records for any abnormality. The interval between CDP and IFX ranged from 1 to 64 months. All patients experienced a progressive reduction in creatinine clearance with CDP. The reduction in creatinine clearance, measured from baseline after three to four courses varied from 10 to 53.7%, after four to seven courses from 19 to 78%, and after seven courses from 12 to 80.5%. In all patients except five, including the HUS patient, creatinine clearance remained above 60 ml/min/m² during IFX therapy. Twelve patients developed hypomagnesemia in the vicinity of 1.4 to 1.6 mg/dl during CDP treatment and required magnesium supplementation. They were asymptomatic and the abnormality did not affect IFX tolerance. Fourteen patients intermittently displayed variable degrees of glycosuria, phosphaturia, and/or proteinuria during IFX therapy. This was considered to be a forma frustre type of Fanconi's syndrome. Approximately 80% of courses of IFX were associated with reversible myelosuppression. No neurologic abnormalities were detected. The abnormalities detected during IFX treatment were not major, did not give rise to symptomatology, and did not require discontinuation of therapy. Renal abnormalities were considered a forma frustre type of Fanconi's syndrome. Provided a creatinine clearance of 60 ml/min/m² is accepted as a prerequisite for treatment, and no major preexisting renal disease is present, IFX is well tolerated by most patients previously exposed to very high cumulative doses of CDP. © 1996 Wiley-Liss, Inc.     

Pharmacokinetics and toxicity of methotrexate in children with Down syndrome and acute lymphocytic leukemia

Children with Down syndrome and acute lymphocytic leukemia (ALL) have poor tolerance to antineoplastic drugs, including methotrexate (MTX). We evaluated MTX pharmacokinetics and toxicity in five patients with Down syndrome and ALL who had received multiple high doses of MTX (1 g/m2). Three control patients without Down syndrome were matched to each case according to sex, race, age, and initial leukocyte count. Median MTX plasma concentrations, measured 42 hours after infusion, were significantly higher in patients with Down syndrome versus control patients (average 0.47 vs 0.24 mumol/L, respectively, P = 0.03). When a 42-hour MTX concentration of 0.5 mumol/L was used to identify patients at risk for toxicity, more courses were considered at high risk for toxicity among patients with Down syndrome (31 of 62, 50%) than in control patients (13 of 214, 6.1%, P less than 0.0001). The average MTX clearance was 64.1 mL/min/m2 in Down syndrome vs an average control value of 80.6 mL/min/m2 (P = 0.13). Toxicity after each high-dose MTX course was graded according to standardized criteria. Grades 2 through 4 gastrointestinal toxicity and grades 3 and 4 hematologic toxicity occurred more frequently in the patients with Down syndrome (36% and 13.4% of courses, respectively) vs the control patients (3.6% and 0.9% respectively, P less than 0.0001 for both). This higher frequency of toxicity occurred despite higher doses and prolonged duration of leucovorin given to all patients with Down syndrome. We conclude that altered MTX pharmacokinetics may contribute to the higher incidence of MTX-induced toxicity seen in patients with Down syndrome.     

Dose modifications and pharmacokinetics of adjuvant cisplatin monotherapy while on hemodialysis for patients with hepatoblastoma

Hepatoblastoma can be associated with chronic kidney disease and genitourinary anomalies. Cisplatin is a key agent for treating hepatoblastoma but renal clearance and toxicity can limit its use in end‐stage renal disease. We present pharmacokinetic data and clinical outcomes using cisplatin on hemodialysis for three patients with hepatoblastoma. All patients were initially treated with surgery and adjuvant cisplatin [1.67 mg/kg (2 patients) or 50 mg/m² (1 patient)]. The patient treated with body surface area‐based dosing had higher exposures and ototoxicity. Treating hepatoblastoma with cisplatin on hemodialysis using 1.67 mg/kg achieved clinical efficacy with minimal morbidity.     

APE chemotherapy for children with relapsed Hodgkin disease: a Pediatric Oncology Group trial

BACKGROUND: MOPP (mechlorethamine, vincristine, procarbazine, prednisone) and ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) are effective therapies for Hodgkin disease (HD) that may cause long-term toxicities in children. APE (cytosine arabinoside, cisplatin, etoposide) is a non-cross-resistant regimen with limited toxicities. We evaluated this regimen for patients with recurrent or refractory disease. METHODS: Patients with recurrent Hodgkin disease who were 相似文献   

高剂量甲氨蝶呤排泄延迟解救措施的病例系列报告

背景：目前国内外对高剂量甲氨蝶呤（MTX）排泄延迟是否应该使用血液透析解救还存在争议。 目的：研究高通量血液透析（HF-HD）对肿瘤患儿MTX清除的有效性。 设计：病例系列报告。 方法：纳入2016年1月至2021年6月在上海交通大学医学院附属上海儿童医学中心血液肿瘤科行MTX化疗后44 h血药浓度＞10 μmol·L-1的连续病例,其中仅使用亚叶酸钙（CF）解救的患儿为非HF-HD组,使用HF-HD+CF解救的患儿为HF-HD组。比较2组患儿的胃肠道、肝功能、肾功能和血液系统毒性等指标。 主要结局指标：肝、肾功能不良反应发生率。 结果：20例发生20例次MTX延迟排泄,非HF-HD组9例,HF-HD组11例,两组患儿美国卫生及公共服务部常见不良事件评价标准v 4.0项目比较,CF组和HF-HD组肌酐、尿酸、ALT、AST、黏膜炎、24 h MTX浓度、MTX浓度恢复正常所需的时间差异均无统计学意义,两组患儿血液系统不良反应发生率差异无统计学意义（P＞0.05）;AST、ALT、发热、黏膜炎、WBC、NE、Hb、PLT异常发生率两组差异无统计学意义。 结论：肾功能正常的肿瘤患儿通过CF解救可有效安全清除MTX,非必要不选择透析。     

Retinal toxicity associated with cisplatin and etoposide in pediatric patients

Cisplatin is an effective chemotherapeutic agent used in the treatment of many pediatric solid tumors. Retinal toxicity is a side effect of the drug reported in adults, but is not well described in pediatric patients. We present the cases of two children treated with cisplatin and etoposide who experienced retinal toxicity documented by visual evoked response (VER) and electroretinogram (ERG). Significantly, both patients had abnormal renal function. The mechanism of visual toxicity induced by cisplatin is unknown but may result from central nervous system (CNS) accumulation of drug after repeated doses, especially with high-dose platinum (HDP) containing regimens. Because clearance of platinum is related to adequate renal-function, patients with any decrease in glomerular filtration rate (GFR) may have delayed platinum excretion. We propose that the patients at greatest risk of cisplatin-induced toxicity are those pretreated with nephrotoxic therapy or those with impairment of renal function from other causes. These patients should have prospective ophthalmologic evaluation especially when treated with HDP containing regimens. Med. Pediatr. Oncol. 28:310–313. © 1997 Wiley-Liss, Inc.     

Isolated late testicular relapse of B‐cell acute lymphoblastic leukemia treated with intensive systemic chemotherapy and response‐based testicular radiation: A Children's Oncology Group study

1 Background

The incidence of isolated testicular relapse (ITR) of acute lymphoblastic leukemia (ALL) has decreased with contemporary treatment strategies, but outcomes are suboptimal with a 58% 5‐year overall survival (OS). This study aimed to improve outcome in patients with ITR of B‐cell ALL (B‐ALL) occurring after 18 months of first clinical remission using intensive systemic chemotherapy and to decrease long‐term sequelae by limiting use of testicular radiation.

2 Procedure

Forty patients in first ITR of B‐ALL were enrolled. Induction (dexamethasone, vincristine, daunorubicin, and intrathecal triple therapy) was preceded by one dose of high‐dose methotrexate (MTX, 5 g/m²). Following induction, 25 of 26 patients who had persistent testicular enlargement underwent testicular biopsy. Eleven had biopsy‐proven disease and received bilateral testicular radiation (24 Gy), whereas twenty‐nine did not.

3 Results

Overall 5‐year event‐free survival (EFS)/OS was 65.0 ± 8.8%/73.1 ± 8.3%, with 5‐year EFS 62.1 ± 11.0% vs. 72.7 ± 14.4% for patients who did not receive radiation therapy (XRT) (n = 29) compared with those who did (n = 11), respectively (P = 0.64). There were six second bone marrow relapses and six second ITRs. The proportion of second relapses was similar in the patients that received testicular radiation and those who did not. However, the 5‐year OS was similar for patients who did not receive XRT (72.6 ± 10.2%) compared with those who did (72.7 ± 14.4%) (P = 0.85).

4 Conclusions

A 5‐year OS rate of 73.1 ± 8.3% was obtained in children with first ITR of B‐ALL occurring after 18 months of CR1 (length of first clinical remission) using intensive chemotherapy and limiting testicular radiation.