Methotrexate, intrathecal

The drug is metabolized rapidly in the liver, kidney, intestinal mucosa, and even red blood cells. Therefore it has a plasma half-life of only 10 min after bolus intravenous application. The major metabolite, uracil arabinoside (ara-U), can be detected in the blood shortly after cytarabine administration. About 80% of the dose is excreted in the urine within 24 h, with less than 10% appearing as cytarabine the remainder is ara-U. After continuous infusion, cytarabine levels in the liquor (cerebro-spinal fluid) approach 40% of that in plasma. Continuous infusion schedules allow maximal efficiency, with uptake peaks of 5-7 pM. It can be administered intrathecally as an alternative to methotrexate. 

There are certain histologic subtypes of diffuse, aggressive NHL that respond less well to treatment with conventional regimens such as CHOP. Burkitt s lymphoma, lymphoblastic lymphoma, mantel cell lymphoma, and primary CNS lymphoma are examples of disease that benefit from more intensive therapy. Regimens such as hyper-CVAD, which alternate cycles of hyperfractionated cyclophosphamide, doxorubicin, vincristine, and dexamethasone with high-dose cytarabine and methotrexate, often are substituted for CHOP. Intrathecal therapy with methotrexate is indicated with documented CNS infiltration of tumor or involvement of the sinuses. The recent appreciation of the etiology of Helicobacter pylori in the etiology of peptic ulcer disease and the association between colonization and mucosal-associated lymphoma (MALT) has spurred... 

Methotrexate 1 5 mg intrathecal, day 2 Above drugs given on courses 2, 4, 6, 8 Relapsed Disease... 

RH is admitted to the pediatric oncology service. She is started on allopurinol and intravenous fluids with sodium bicarbonate to prevent tumor lysis syndrome. According to her risk status, she will receive a three-drug induction with vincristine, dexamethasone, and pegylated asparaginase. She also will receive intrathecal (IT) chemotherapy for CNS prophylaxis with methotrexate, cytarabine, and hydrocortisone. 

C, cytarabine ASP, asparaginase CALCB, Cancer and Leukemia Croup B CNS, central nervous system CTX, cyclophosphamide DEX, dexamethasone DNR, daunorubicin DOX, doxorubicin IT, intrathecal captopurine MTX, methotrexate PRED, prednisone TG, thioguanine VCR, vincristine. 

CNS prophylaxis relies on intrathecal chemotherapy (e.g., methotrexate, cytarabine, and corticosteroids), systemic... 

Pegaspargase 2,500 units/m2 per dose IM for 1 dose or asparaginase 6,000 units/m2 per dose IM Mon, Weds, and Fri for 6 doses Intrathecal methotrexate weekly for 2-4 doses Consolidation (1 month)... 

Mercaptopurine 50-75 mg/m2 per dose orally at bedtime for 28 days Vincristine 1.5 mg/m2 per dose (max 2 mg) IV on day 0 Intrathecal methotrexate weekly for 1-3 doses Patients with CNS or testicular disease may receive radiation Interim maintenance (1 or 2 cycles) (2 months)... 

The prevalence of CNS disease at diagnosis of AML ranges from 5% to 30% in various treatment series. Features associated with the risk of CNS leukemia include hyperleukocytosis, monocytic or myelomonocytic leukemia (FAB M4 or M5), and young age. In most cases, intrathecal cytarabine with or without methotrexate and systemic high-dose cytarabine provide adequate CNS prophylaxis.3 Results from studies have shown that patients with CNS disease at diagnosis can be cured with intrathecal therapy alone without the use of cranial irradiation.11... 

Diluents Do not use methotrexate formulations and diluents containing preservatives for intrathecal or high-dose methotrexate therapy. 

Skin reactions Severe, occasionally fatal skin reactions have been reported following single or multiple doses of methotrexate. Reactions have occurred within days of oral, IM, IV, or intrathecal methotrexate administration. Recovery has been reported with discontinuation of therapy. 

The existence of the blood-brain barrier is an important consideration in the chemotherapy of neoplastic diseases of the brain or meninges. Poor drug penetration into the CNS has been a major cause of treatment failure in acute lymphocytic leukemia in children. Treatment programs for this disease now routinely employ craniospinal irradiation and intrathecally administered methotrexate as prophylactic measures for the prevention of relapses. The testes also are organs in which inadequate antitumor drug distribution can be a cause of relapse of an otherwise responsive tumor. 

Other routes of administration can be employed in certain situations. Methotrexate and cytarabine are given intrathecally or intraventricularly to prevent relapses in the meninges in acute lymphocytic leukemia and to treat carcinomatous meningitis. Thiotepa and bleomycin have been administered by intravesical instillation to treat early bladder cancers. Fluorouracil can be applied topically for certain skin cancers. 

Methotrexate is one of the few anticancer drugs that can be safely administered intrathecally for the treatment of meningeal metastases. Its routine use as prophylactic intrathecal chemotherapy in acute lymphoblastic leukemia has greatly reduced the incidence of recurrences in the CNS and has contributed to the cure rate in this disease. Daily oral doses of methotrexate are used for severe cases of the nonneoplastic skin disease psoriasis (see Chapter 41), and methotrexate has been used as an immunosuppressive agent in severe rheumatoid arthritis. 

Cytarabine is used in the chemotherapy of acute myelogenous leukemia, usually in combination with an anthracycline agent, thioguanine, or both. It is less useful in acute lymphoblastic leukemia and the lymphomas and has no known activity against other tumors. It has been used intrathecally in the treatment of meningeal leukemias and lymphomas as an alternative to methotrexate. 

BFM and St. Jude protocols, are that on BFM protocols no topoisomerase 11 inhibitors are given in close association with thiopurines and, finally, that on BFM protocols no intrathecal triple therapy (methotrexate, cytarabine, and a glucocorticoid) are given concurrent with cranial radiotherapy and 6-MP. Another important toxicity issue associated with TPMT status relates to the above-described VOD-like symptoms of the liver in childhood ALL patients treated with 6-TG on the British MRC ALL97 trial (209). In this trial, TPMT activity was significantly lower in children in whom VOD developed while no differences in RBC 6-TGN levels were described. This information in association with ongoing research efforts will help to develop a better understanding of 6-TG-associated liver toxicity and may help to identify those individuals upfront who should not be administered 6-TG. 

The main folate antagonist is methotrexate, an analogue of folic acid. Methotrexate competitively inhibits dihydrofolate reductase, the enzyme responsible for the synthesis of purine and pyramidine from folic acid. Trimetrexate, a methotrexate analogue, is useful in treating methotrexate-resistant tumours. It is also used to treat Pneumocystis carinii infections. Methotrexate is usually given orally, but may also be given intravenously or intrathecally. In addition to its use in cancer therapy, it is used in the treatment of psoriasis. Methotrexate can cause an obstructive nephropathy due to its precipitation in the renal calyx. 

Methotrexate acts by inhibition of dihydrofolate reductase, the enzyme requisite for the reduction of dihydrofolic acid (3) to 5,6,7,8-tetrahydrofolic acid (4). In turn, (4) is a precursor to a series of enzyme cofactors (5-7) essential for the transfer of one carbon unit necessary for the biosynthesis of purines and pyrimidines and hence, ultimately, DNA. As an inhibitor of dihydrofolate reductase, methotrexate kills cells during the S phase of the cell cycle, when the cells are in the log phase of growth. Unfortunately, this cytotoxicity is non-selective, and rapidly proliferating normal cells, e.g., gastrointestinal epithelium cells and bone marrow, are dramatically affected as well. In addition, recent use of high dose methotrexate therapy with leucovorin rescue has led to additional clinical problems arising from a dose-related nephrotoxic metabolite, 7-hydroxy methotrexate (8). Finally, the very polar nature of methotrexate renders it virtually impenetrable to the blood-brain barrier, which can necessitate direct intrathecal injection in order to achieve therapeutic doses for the treatment of CNS tumours. 

Acute lymphoid leukemia During the initial phase, vincristine and prednisone are used. Methotrexate and mercaptopurine are used for maintenance therapy. In addition, methotrexate is given intrathecally, with or without radiotherapy, to prevent meningeal leukemia. 

Methotrexate 2.5-5 mg/d orally (Rheumatrex) 10 mg intrathecally (Folex) once or twice weekly Mucositis, diarrhea, bone marrow depression with leukopenia and thrombocytopenia... 

Methotrexate is administered by the intravenous, intrathecal, or oral route. Up to 90% of an oral dose is excreted in the urine within 12 hours. The drug is not subject to metabolism, and serum levels are therefore proportionate to dose as long as renal function and hydration status are adequate. Dosages and toxic effects are listed in Table 55-3. The effects of methotrexate can be reversed by administration of leucovorin (citrovorum factor). Leucovorin rescue has been used with accidental overdose or experimentally along with high-dose methotrexate therapy in a protocol intended to rescue normal cells while still leaving the tumor cells subject to its cytotoxic action. 

Intrathecal/lntraventricular It is sometimes necessary to introduce drugs directly into the cerebrospinal fluid (CSF), such as methotrexate in acute lymphocytic leukemia (see p. 379). 

The size of the central nervous system (CNS), which is disproportionately larger in infants as compared to adults, has a quantifiable effect on drug concentrations achieved in the cerebrospinal fluid (CSF) after intrathecal administration of drugs, and influences the dosing of intrathecal therapy in infants and young children. For example, CSF methotrexate concentrations after... 

FIGURE 23.10 (A) Cerebrospinal fluid (CSF) methotrexate N(MtX) concentrations after an intrathecal dose of 12 mg/m. Children designated as open squares and adolescents designated as closed circles had lower concentrations than did adults represented as open circles, and lower concentrations were associated with a higher risk of treatment failure. (B) Growth rate of central nervous system volume relative to whole body growth represented by body surface area. (Reproduced with permission from Bleyer WA. Cancer Treat Rep 1977 61 1419-25.)... 

FIGURE 23.11 Percentage change in the dose of intrathecal methotrexate using the age-adjusted dosing schedule (<1 yr, 6 mg 1 yr, 8 mg 2 yr, 10 mg > 3 yr, 12 mg) relative to administering a 12-mg/m dose adjusted to body surface area (horizontal line at 0%). 

Bleyer WA. Clinical pharmacology of intrathecal methotrexate. II. An improved dosage regimen derived from age-related pharmacokinetics. Cancer Treat Rep 1977 61 1419-25. 

Bleyer WA, Coccia PF, Sather HN, Level C, Lukens J, Niebrugge DJ et al. Reduction in central nervous system leukemia with a pharmacokinetically dervived intrathecal methotrexate dosage regimen. J Clin Oncol 1983 1 317-25. 

Plasmapheresis is effecdve in patients with severe neuropsychiatric SLE refractory to conventional treatment. Intrathecal methotrexate and dexamethasone is also beneficial to those patients (Dong et al., 2001 Baca et al., 1999). Positive results of a phase I/n trial of autologous hematopoietic stem cell transplantadon (AHSCT) at Northw estem University in Chicago, UL has led to a phase HI ASCT dial. As with other similar dials involving autoimmune disease, the ASCT dial is designed to include standard of care PV pulse cyclophosphamide (Burt et al., 2003b). 

Dong Y, Zhang X, Tang F, Tian X, Zhao Y, Zhang F (2001) Intrathecal injection with methotrexate plus dexamethasone in the treatment of central nervous system involvement in systemic lupus erythematosus. Chin Med J (Engl) 114 764—766. 

Acute lymphocytic leukaemia (ALL) nducii on vincristine + prednisolone + asparaginase z doxorubicin CNS prophyfajeis intrathecal methotrexate with cranial irradiation z systemic high-dose methotrexate with folinic acid rescue intrathecal cytarabine intrathecal hydrocortisone / d<11 fIterance, methotrexate mercapcopurineibone marrow transplant... 

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