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.     

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.     

A phase II study of radioimmunotherapy with intraventricular 131I‐3F8 for medulloblastoma

1 Background

High‐risk and recurrent medulloblastoma (MB) is associated with significant mortality. The murine monoclonal antibody 3F8 targets the cell‐surface disialoganglioside GD2 on MB. We tested the efficacy, toxicity, and dosimetry of compartmental radioimmunotherapy (cRIT) with intraventricular ¹³¹I‐labeled 3F8 in patients with MB on a phase II clinical trial.

2 Methods

Patients with histopathologically confirmed high‐risk or recurrent MB were eligible for cRIT. After determining adequate cerebrospinal fluid (CSF) flow, patients received 2 mCi (where Ci is Curie) ¹²⁴I‐3F8 or ¹³¹I‐3F8 with nuclear imaging for dosimetry, followed by up to four therapeutic (10 mCi/dose) ¹³¹I‐3F8 injections. Dosimetry estimates were based on serial CSF and blood samplings over 48 hr plus region‐of‐interest analyses on serial imaging scans. Disease evaluation included pre‐ and posttherapy brain/spine magnetic resonance imaging approximately every 3 months for the first year after treatment, and every 6–12 months thereafter.

3 Results

Forty‐three patients received a total of 167 injections; 42 patients were evaluable for outcome. No treatment‐related deaths occurred. Toxicities related to drug administration included acute bradycardia with somnolence, headache, fatigue, and CSF pleocytosis consistent with chemical meningitis and dystonic reaction. Total CSF absorbed dose was 1,453 cGy (where Gy is Gray; 350.0–2,784). Median overall survival from first dose of cRIT was 24.9 months (95% confidence interval [CI]:16.3–55.8). Patients treated in radiographic and cytologic remission were at a lower risk of death compared to patients with radiographically measurable disease (hazard ratio: 0.40, 95% CI: 0.18–0.88, P = 0.024).

4 Conclusions

cRIT with ¹³¹I‐3F8 is safe, has favorable dosimetry to CSF, and when added to salvage therapy using conventional modalities, may have clinical utility in maintaining remission in high‐risk or recurrent MB.     

Delayed short‐term administration of granulocyte colony‐stimulating factor is a good mobilization strategy for harvesting autologous peripheral blood stem cells in pediatric patients with solid tumors

PBSCs have become the preferred source of autologous stem cells for supporting high‐dose chemotherapy in childhood solid tumors. The aims of this retrospective study were to examine the optimal timing for administration of G‐CSF after chemotherapy and to identify the patients from whom an optimal dose of PBSCs can be harvested. We evaluated the timing of G‐CSF administration for harvesting PBSCs in patients with childhood solid tumors. G‐CSF was administered immediately after chemotherapy in eight patients (11 harvests, long‐term group) and following recovery from hematological nadirs in 17 patients (21 harvests, short‐term group). The median duration of G‐CSF administration was 22 vs. 5 days, respectively (p < 0.005), and the dose of harvested CD34⁺ cells (×10⁶/kg) was 1.4 vs. 2.9, respectively (p = 0.023). Our results suggest that short‐term G‐CSF administration is a good strategy for harvesting PBSCs in these patients.     

Dextromethorphan is effective in the treatment of subacute methotrexate neurotoxicity

Methotrexate-induced neurotoxicity (MTX-Ntox) is a frequent complication of methotrexate (MTX) therapy for patients with both malignant and inflammatory diseases. MTX-Ntox can occur after intrathecal MTX or after low-, intermediate-, or high-dose systemic administration. Symptoms can present in the acute, subacute, or late setting form, and can range from affective disorders, malaise, and headaches, to somnolence, focal neurologic deficits, and seizures. While the pathogenesis of MTX-Ntox is likely multifactorial, one potential biochemical pathway leading from MTX to neurotoxicity involves the folate dependent remethylation of homocysteine (Hcy). MTX therapy is known to cause elevations of both plasma and CSF Hcy. Hcy is directly toxic to vascular endothelium and it and its metabolites are excitatory agonists of the N-methyl-D-aspartate (NMDA) receptor. Competitive or noncompetitive antagonists might afford protection from or reversal of MTX-Ntox. Using high-performance liquid chromatography (HPLC) with coulometric electrochemical detection, the authors measured CSF Hcy in sequential patients with severe subacute MTX-Ntox. CSF Hcy was higher in these patients (n = 9, median = 0.93 microM) than in asymptomatic patients (n = 11, median 0.2 microM, p < .01). Five patients with severe subacute MTX-Ntox (most with dysarthria and/or hemiplegia) were treated with 1-2 mg/kg oral dextromethorphan (DM), a noncompetitive antagonist of the N-methyl-1-aspartate (NMDA) receptor. All five had resolution of symptoms. These data provide additional clinical support for elevated CSF Hcy in the induction of MTX-Ntox through activation of the NMDA-receptor. These data provide support for a placebo-controlled clinical trial to examine the ability of DM to prevent or alleviate MTX-Ntox.     

Ambulatory high-dose methotrexate administration among pediatric osteosarcoma patients in an urban, underserved setting is feasible, safe, and cost-effective

Background

We describe the safety, feasibility, and provide a cost‐estimate of outpatient high‐dose methotrexate administration (HDMTX) among an urban, underserved population.

Procedure

A retrospective analysis of ambulatory HDMTX administration among osteosarcoma patients, at Montefiore Medical Center's Children's Hospital (Bronx, NY) was performed. HDMTX (12 g/m²) was given intravenously (IV) over 4 hr after urine alkalinization. Patients were discharged home to continue IV hydration and alkalinization delivered via a home infusion pump. Families were instructed to monitor urine pH overnight and management was adjusted according to our institution's treatment algorithm until MTX level ≤0.1 µmol/L. A cost estimate was performed to assess the difference in costs for outpatient versus hypothetical inpatient administrations.

Results

Of the 97 ambulatory HDMTX administrations, 99% were successfully completed. One patient failed outpatient administration secondary to home infusion pump malfunction. This patient successfully completed subsequent courses as an outpatient. Most patients (72%) had a MTX level of <10 µmol/L at 24 hr post‐HDMTX. No patients were found to have a MTX level of >50 µmol/L at 24 hr. About 26% of courses were associated with grade III or IV neutropenia, 4% were associated with grade III or IV thrombocytopenia and 1% were associated with grade III/IV leukopenia. Compared to a hypothetical hospital inpatient stay, the hospital costs for ambulatory HDMTX were an average of $1400 less per cycle.

Conclusion

Ambulatory HDMTX administration among an underserved, urban population is safe, feasible, and cost‐effective. Pediatr Blood Cancer. 2010;55:1296–1299. © 2010 Wiley‐Liss, Inc.     

Safety and feasibility of granulocyte colony‐stimulating factor (G‐CSF) primed bone marrow (BM) using three days of G‐CSF priming as stem cell source for pediatric allogeneic BM transplantation

There are limited data on the optimal dosing and schedule of G‐CSF priming prior to BM harvest. We evaluated the safety and efficacy of three days of G‐CSF of primed BM from related pediatric donors. Forty‐five children were treated. All donors received 5 μg/kg per day of G‐CSF as a single subcutaneous injection for three consecutive days prior to the BM harvest. The median age of the donors was seven yr (range, 0.8–18) and no donor experienced major adverse events related to G‐CSF administration. The median age for the recipients was five yr (0.3–16 yr). Thirty‐five patients had non‐malignant disorders. The median dose of nucleated (TNC) and CD34+, CD3 cells infused per recipient weight was 5.4 × 10⁸/kg (range, 0.61–17), 4.7 × 10⁶/kg (range, 1.6–19), and 43.8 × 10⁶/kg (range, 1.8–95), respectively. All patients achieved neutrophil and platelets engraftment, at a median of 15 (range, 10–22) and 23 days (range, 13–111), respectively. At a median follow up of 60 months (range 12–100), the estimated five yr overall and EFS was 91% and 80%, respectively. Collection of BM following three days of G‐CSF priming from pediatric donors is safe and results in high TNC and CD34+ cell yield.     

Nephrolithiasis in pediatric hematopoietic cell transplantation with up to 40 years of follow‐up

Background

Kidney stones have been reported to occur after childhood cancer, but little is known about kidney stones in children following hematopoietic cell transplantation (HCT). The objective of this retrospective study was to determine risk factors for the development of kidney stones and to describe the prevalence among survivors.

Procedure

The study included 1,343 childhood HCT patients. Mean follow‐up was 15.8 (1.0–40.0) years. Patients were treated with total body irradiation (TBI) (n = 948) or non‐TBI regimens. Methotrexate (MTX) for acute graft‐versus‐host disease (GVHD) prophylaxis was given as long‐course (n = 360), short‐course (n = 626), or none (n = 357). Prednisone for chronic GVHD therapy was received by 525 patients. Multivariate Cox regression models were used to estimate the hazard ratio (HR) of risk factors associated with kidney stones.

Results

Kidney stones developed in 51 patients, a median of 9.9 (0.2–29.4) years after first HCT, with a 30‐year cumulative incidence of 7.4%. Risk factors associated with kidney stones were TBI (HR = 2.2; P = 0.03), age at HCT (12–18 vs. <6 years, HR = 2.7; P = 0.01), MTX (long vs. none, HR = 3.6; P = 0.02), and prednisone (HR = 2.2; P = 0.008). Among 868 survivors, the prevalence of a history of kidney stones was 4.7%.

Conclusions

Survivors of childhood HCT have an increased risk of developing kidney stones. Pediatr Blood Cancer 2014;61:417–423. © 2013 Wiley Periodicals, Inc.     

Non‐immediate‐reading skin tests and prolonged challenges in non‐immediate hypersensitivity to beta‐lactams in children

Background

A minority of children reporting non‐immediate reactions to beta‐lactams (BLs) are allergic. Allergy workup usually includes late‐reading (48‐72 hours) skin tests (ST) and short (1‐3 days) drug provocation tests (DPT), regardless of the chronology of the index reaction. The sensitivity of hyper‐late‐reading (≥6‐7 days) ST and of prolonged DPT for the diagnosis of non‐immediate hypersensitivity to BLs is yet to be determined.

Objectives

To establish the diagnostic values of late‐reading ST and hyper‐late‐reading ST and of prolonged DPT in children reporting non‐immediate reactions to BLs.

Methods

Prospective assessment of children reporting non‐immediate reactions to BLs with late‐ and additional hyper‐late‐reading intradermal (ID) and patch tests, and if negative, with prolonged DPT.

Results

Five hundred and fifty children reporting reactions to a single or several BLs (674 suspected BLs) were included. Non‐immediate hypersensitivity to BLs was diagnosed in 63 children (11.5%), reporting 66 reactions (9.8%), based on responses in ST (n = 17, 25.8%: 5 to ID, 8 to patch tests, and 4 to both tests), DPT (n = 43, 65.2%), and clinical history (n = 6, 9.1%), including 3/9 children with severe cutaneous adverse reactions. Skin test positivity was observed after the 6‐7th day in 14/17 children, and DPT positivity after a median time of 3 days. No severe reaction was observed after ST or during prolonged DPT.

Conclusion

Additional hyper‐late‐reading of ST enhanced their positivity. However, their overall sensitivity remained weak, especially in non‐severe cases. Prolonged DPT are safe and may improve the performance of DPT in the diagnosis of non‐immediate hypersensitivity to BLs.     

Prolonged 14‐day continuous infusion of high‐dose ifosfamide with an external portable pump: Feasibility and efficacy in refractory pediatric sarcoma

Background

Ifosfamide is currently used to treat pediatric sarcomas and increasing its dosage may be associated with a better response rate. Prolonged continuous infusion seems an attractive administration modality.

Methods

Ifosfamide 14 g/m² (with mesna 14 g/m²) was administered through an ambulatory portable pump over 14 days as a continuous infusion, starting every 3 weeks, in 14 patients with relapsing sarcomas. No growth factors were given.

Results

Acute grade 3 hematological toxicity was observed in only 13/66 cycles and red cell transfusions were given in two patients. Hematuria and dysuria occurred in three cases. The response rate was: five partial responses, five stable disease. The median time to progression was 3 months (range: 2–19 months). The best response rate was seen for synovial sarcoma and Ewing sarcoma.

Conclusion

Prolonged 14‐day continuous infusion of high‐dose ifosfamide is well tolerated. Potentially interesting preliminary responses in pediatric patients already treated with ifosfamide are reported. Pediatr Blood Cancer. 2010;55:617–620. © 2010 Wiley‐Liss, Inc.     

A Rare Complication of Intrathecal Methotrexate in a Child with Acute Lymphoblastic Leukemia

Methotrexate (MTX) is an essential component of chemotherapy for childhood acute lymphoblastic leukemia (ALL). Both intravenous and most commonly intrathecal routes of MTX have been implicated in acute, subacute, and chronic neurotoxicity syndromes. Subacute MTX neurotoxicity occurs within days to weeks after the intravenous or intrathecal therapy and characterized by a distinct presentation with remarkable clinical resemblance to stroke, including hemiparesis, hemisensory deficits, aphasia, dysarthria, dysphagia, and diplopia. Herein the authors describe the clinical and typical neuroimaging features of a female patient with ALL who presented with subacute MTX neurotoxicity that rapidly progressed to a severe clinical condition in a few hours but eventually resolved completely with dexamethasone and folinic acid. Subacute MTX neurotoxicity is a transient neurological dysfunction that should be considered in patients presenting with stroke-like and various neurological symptoms 10 to 14 days after intrathecal therapy and diffusion-weighted magnetic resonance imaging should be undertaken for the correct diagnosis and exclusion of possible ischemic infarct. Discontinuation of subsequent intrathecal MTX therapies should be considered in severe cases and treatment with dexamethasone and folinic acid may help to resolve the symptoms.     

A rare complication of intrathecal methotrexate in a child with acute lymphoblastic leukemia

Methotrexate (MTX) is an essential component of chemotherapy for childhood acute lymphoblastic leukemia (ALL). Both intravenous and most commonly intrathecal routes of MTX have been implicated in acute, subacute, and chronic neurotoxicity syndromes. Subacute MTX neurotoxicity occurs within days to weeks after the intravenous or intrathecal therapy and characterized by a distinct presentation with remarkable clinical resemblance to stroke, including hemiparesis, hemisensory deficits, aphasia, dysarthria, dysphagia, and diplopia. Herein the authors describe the clinical and typical neuroimaging features of a female patient with ALL who presented with subacute MTX neurotoxicity that rapidly progressed to a severe clinical condition in a few hours but eventually resolved completely with dexamethasone and folinic acid. Subacute MTX neurotoxicity is a transient neurological dysfunction that should be considered in patients presenting with stroke-like and various neurological symptoms 10 to 14 days after intrathecal therapy and diffusion-weighted magnetic resonance imaging should be undertaken for the correct diagnosis and exclusion of possible ischemic infarct. Discontinuation of subsequent intrathecal MTX therapies should be considered in severe cases and treatment with dexamethasone and folinic acid may help to resolve the symptoms.     

Dose‐escalation is needed for gross disease in high‐risk neuroblastoma

1 Background

Locoregional failure is common after subtotal resection in high‐risk neuroblastoma. Although a dose of 21 Gy radiation therapy (RT) is standard for treatment of high‐risk neuroblastoma after gross total resection, the dose needed for local control of patients with gross residual disease at the time of RT is unknown. We sought to evaluate local control after 21–36 Gy RT in patients with high‐risk neuroblastoma undergoing subtotal resection.

2 Methods

All patients with high‐risk neuroblastoma who received RT to their primary site from 2000 to 2016 were reviewed. Of the 331 patients who received consolidative RT to their primary site, 19 (5.7%) underwent subtotal resection and were included in our analysis. Local failure (LF) was correlated with biologic prognostic factors and dose of RT.

3 Results

Median follow‐up among surviving patients was 6.0 years. Median RT dose was 25 Gy (range, 21 Gy–36 Gy). The 5‐year cumulative incidence of LF among all patients was 17.2%. LF at 5 years was 30% in those who received <30 Gy versus 0% in those who received 30–36 Gy (P = 0.12). There was a trend towards improved local control in patients with tumor size ≤10 cm at diagnosis (P = 0.12). The 5‐year event‐free and overall survival were 44.9% and 68.7%, respectively.

4 Conclusion

After subtotal resection, patients who received less than 30 Gy had poor local control. Doses of 30–36 Gy are likely needed for optimal control of gross residual disease at the time of consolidative RT in high‐risk neuroblastoma.     

Observation study showed that the continuity of skin‐to‐skin contact with low‐birthweight infants in Uganda was suboptimal

Aim

Kangaroo mother care (KMC) is a safe and effective method of reducing neonatal mortality in resource‐limited settings, but there has been a lack of data on the duration of skin‐to‐skin contact (SSC) in busy, low‐resource newborn units. Previous studies of intermittent KMC suggest the duration of SSC ranged from 10 minutes to 17 hours per day.

Methods

This was an observational study of newborn infants born weighing less than 2000 g, which collected quantitative data on SSC over the first week after birth. The study took place in July 2016 in the newborn unit of a low‐resource facility in Uganda.

Results

The mean daily duration of SSC over the first week after birth was three hours. This differed significantly from the World Health Organization recommendation of at least 20 hours of SSC per day. SSC was provided by mothers most of the time (73.5%), but other family members also took part, especially on the day of birth.

Conclusion

Our study found a disappointingly low daily duration of SSC in this Ugandan newborn unit. However, advocacy and community education of SSC may help to decrease the stigma of KMC, improve overall acceptance and reduce the age at SSC initiation.

     

儿童急性白血病应用大剂量甲氨蝶呤严重并发症3例临床分析及文献复习

目的探讨儿童白血病（ALL）应用大剂量甲氨蝶呤（HD-MTX）严重并发症的临床特点、发生机制及预防处理措施。方法总结3例在本院确诊并按ALL治疗方案规范化疗的儿童急性淋巴细胞白血病应用HD．MTX后出现严重并发症病例的临床特点并复习文献。结果3例患儿均为学龄期儿童、急性淋巴细胞白血病应用HD．MTx（5g／m2）期间发生严重高甲氨蝶呤血症,治疗期间严密监测血药浓度,持续水化、碱化以及多种方式四氢叶酸钙解救但甲氨蝶呤排泄延迟,2～3周后血清甲氨蝶呤浓度仍明显高于中毒浓度,化疗后2周均合并严重骨髓抑制,2例出现表皮松解、1例消化道溃疡,均因继发感染及多脏器损害并发症死亡。结论甲氨蝶呤体内的代谢受到多种因素影响,持续高血药浓度可造成严重并发症,对儿童ALL应用HD．MTX应根据细胞免疫学表型、细胞遗传学及甲氨蝶呤静脉滴注后不同时段的血药浓度及药物代谢酶相关基因情况采用个体化治疗。     

How long can folinic acid rescue be delayed after high‐dose methotrexate without toxicity?

To determine the optimal time of folinic acid rescue after methotrexate (MTX) treatment in patients with ALL, we selected and evaluated relevant studies that included doses, rescue delay, and side effects. Rescue at 42–48 hours resulted in considerable toxicity, except when low doses of MTX were used (1 g/m²) or serum MTX levels remained consistently low at 24, 30, and 36 hours. Rescue started at 30–36 hours was safe. In the absence of evidence that later rescue improves prognosis, we suggest that folinic acid rescue (105 mg/m²) be started no later than 36 hours from the start of MTX (5–6 g/m²). Pediatr Blood Cancer 2014;61:7–10. © 2013 Wiley Periodicals, Inc.     

Results of AIEOP LNH-97 protocol for the treatment of anaplastic large cell lymphoma of childhood

Background

Anaplastic large cell lymphoma (ALCL) represents approximately 15% of all pediatric non‐Hodgkin lymphomas (NHL). It has distinct clinical features, including frequent involvement of extranodal sites and rare localization to the central nervous system (CNS). Despite varying treatment approaches the outcome of patients with ALCL has not significantly improved during the last two decades.

Procedure

From October 1997 to beginning of 2000, newly diagnosed ALCL patients were enrolled into AIEOP LNH‐97 protocol for ALCL. Thereafter and until 2007, only CNS positive patients were included. AIEOP LNH‐97 was based on the BFM‐95 schema for ALCL and included six high‐dose chemotherapy courses. CNS prophylaxis was obtained with one intrathecal injection of chemotherapy in each course, whereas treatment of CNS involvement included three intrathecal injections without irradiation.

Results

Thirty‐two patients were eligible for the study. Lymph‐node disease was the most frequent localization (69% of the cases), followed by mediastinal (25%), CNS (22%), bone marrow (16%), and skin (13%) involvement. Probabilities of overall survival (OS) and of event‐free survival (EFS) at 5 years for the whole population were 87% (SE 6%) and 68% (SE 8%), respectively.

Conclusions

This study confirmed that short pulse chemotherapy is an efficacious treatment option for first line therapy of pediatric ALCL, and that dose intensity may have some relevance for outcome, but not in all of the patients. Refinement and optimization of therapy strategies for ALCL may originate from a combination of clinical and biological prospective studies, as those in the pipeline of current international collaboration. Pediatr Blood Cancer 2012; 59: 828–833. © 2012 Wiley Periodicals, Inc.     

Recurrent intrathecal methotrexate induced neurotoxicity in an adolescent with acute lymphoblastic leukemia: Serial clinical and radiologic findings

Systemic and intrathecal methotrexate (MTX) are integral components of acute lymphoblastic leukemia (ALL) therapy, but can be associated with neurotoxicity. We describe here the case of an adolescent male with T-cell ALL who developed recurrent episodes of subacute neurotoxicity characterized by slurred speech, emotional lability, and hemiparesis after intrathecal MTX administration. Serial magnetic resonance imaging with diffusion-weighted imaging showed recurrent areas of restricted diffusion within cerebral hemispheric white matter, which correlated chronologically with the administration of intrathecal therapy and severity of clinical symptoms. Resolution of diffusion abnormalities did not preclude further toxicity and a large lesion could cause persisting symptoms.     

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.