Chemotherapy intrathecal

DQ is a 57-year-old man who came to the emergency room because of shortness of breath. A radiographic examination demonstrates a large mass pressing on the bifurcation of the main stem bronchus. A biopsy demonstrates an aggressive lymphoma a five-drug chemotherapy regimen with both intravenous and intrathecal chemotherapy will start today. 

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. 

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

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. 

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. 

The data on reported cases of neurological disorders after intrathecal chemotherapy with methotrexate or cytosine arabinoside that could be attributed to benzyl alcohol or to other preservatives have been reviewed in the context of a case of flaccid paraplegia after intrathecal administration of cytosine arabinoside diluted in bacteriostatic water containing 1.5% benzyl alcohol (1). Most commonly, flaccid paraparesis, with absent reflexes, developed rapidly, often with pain and anesthesia. Very often there was full recovery. The prognosis depended mainly on the concentration of the preservative and on the time of exposure. In some cases, the paralysis ascended to cause respiratory distress, cardiac arrest, and death. Only preservative-free sterile CSF substitute or saline, or preferably the patient s own CSF, should be used to dilute chemotherapeutic agents (SEDA-11, 475). 

Hahn AF, Feasby TE, Gilbert JJ. Paraparesis following intrathecal chemotherapy. Neurology 1983 33(8) 1032-8. 

High-dose chemotherapy with cyclophosphamide, vincristine, prednisolone, and intrathecal methotrexate given for post-transplant lymphoproliferative disease was suggested to have favored the occurrence of acute ciclosporin neurotoxicity (headache, fever, seizures, and visual agnosia) in a 9-year-old cardiac transplant patient (239). Ciclosporin serum concentrations were normal and a further similar episode occurred on ciclosporin readministration. 

Lesnik PG, Ciesielski KT, Hart BL, Benzel EC, Sanders JA. Evidence for cerebellar-frontal subsystem changes in children treated with intrathecal chemotherapy for leukemia enhanced data analysis using an effect size model. Arch Neurol 1998 55(12) 1561-8. 

Guidance on the safe administration of intrathecal chemotherapy has been issued in the UK (91), following a case in which vincristine was fatally injected into the cerebrospinal fluid (92). 

NHS Executive. National guidance on the safe administration of intrathecal chemotherapy. HSC 2000 022. 

High risk. Medications, procedures, processes, and disease states for which there is a greater chance for adverse outcomes (e.g., chemotherapy administration, intravenous potassium use, intrathecal injections, anticoagulation, medications with a narrow therapeutic index, and care of immunocompromised patients). 

Because the high risk of central nervous system relapse in ALL, all patients require prophylactic therapy to prevent CNS disease. The choice for therapy includes a combination of the following cranial irradiation and single-agent intrathecal chemotherapy, triple-drug intrathecal chemotherapy, or high-dose systemic chemotherapy that crosses the blood-brain barrier. 

The goal of CNS prophylaxis is to eradicate undetectable leukemic cells from the CNS. Leukemic meningitis is more easily prevented than treated. Once CNS relapse has occnrred, patients are at increased risk of bone marrow relapse and death from refractory leukemia. Initial trials in childhood ALL in the 1960s established craniospinal irradiation as the standard for prevention of CNS relapse." However, this approach was associated with long-term seqnelae including neuropsychological deficits, precocious puberty, osteoporosis, thyroid dysfunction, an increased incidence of brain tumors, short stature, and obesity. Subseqnent trials have demonstrated that irradiation may be replaced by freqnent administration of intrathecal chemotherapy in most children with ALL."... 

Tretinoin, an oral vitamin A analog, is usually given orally in a dose of 45 mg/m per day, as a single dose or divided into two doses, given after a meal. Tretinoin-based regimens achieve CR rates as high as 95%in APL patients within 1 to 3 months. Tretinoin does not cross the blood-brain barrier therefore leukemic meningitis should be treated with conventional intrathecal chemotherapy. 

Pennybacker J, Russell DS Necrosis of the brain due to radiation therapy clinical and pathological observations. J Neurol Neurosurg Psychiatry 11 183-198, 1948 Peylan-Ramu N, Poplack DG, Pizzo PA, et al Abnormal CT scans of the brain in asymptomatic children with acute lymphocytic leukemia after prophylactic treatment of the central nervous system with radiation and intrathecal chemotherapy. N Engl J Med 298 815-818,1978... 

Blasberg, R., C. Patlak, and J. Fenstermacher, Intrathecal chemotherapy brain tissue profiles after ventriculocisternal perfusion. Journal of Pharmacology and Experimental Therapeutics, 1975, 195, 73-83. 

Henderson, R.D., et al.. Posterior leukoencephalopathy following intrathecal chemotherapy with MRA-documented vasospasm. Neurology, 2003. 60(2) p. 326-8. 

In hospital, many patients have a venous cannula and systemic drugs not given orally are usually given intravenously (i.v.) rather than subcutaneously (s.c.) or intramuscularly (i.m.). Other parenteral routes of administration (intrathecal, epidural, intra-osseous, subcutaneous infusion, intra-arterial, intracardiac, etc.) can be used by trained staff but they are restricted to marginal use (e.g. palliative care, emergency situations such as resuscitation). Parenteral routes allow the administration of drugs to unconscious, uncooperative, dehydrated patients and for chemotherapy. Drugs that are inactive or irritable via other routes can also be administered via this route. The dose administered is complete and accurate. There is a fast onset of therapeutic action as the systemic effect is direct, with predictable bioavailability. There is no first-pass metabolism. Nevertheless, once administered, the effect cannot be reversed (e.g. in case of overdose). 

At approximately 17.00 hrs on Thursday 4th January 2001, Mr David James, a day case patient on Ward E17 at the Queen s Medical Centre Nottingham (QMC), was prepared for an intrathecal (spinal) administration of chemotherapy as part of his medical maintenance programme following successful treatment of leukaemia. 

Nervous system Methotrexate-induced myelopathy occurred in a woman with breast cancer and meningeal carcinomatosis, who was treated with intrathecal chemotherapy with methotrexate 15 mg and dexamethasone [70 ]. Five days after the last cycle, she developed bloody diarrhea, vomiting, urinary retention, and pancytopenia. While she recovered, progressive neurological deficits emerged. High doses of the key metabolites of the methyl-transfer pathway (adenosylmethio-nine, folinate, cyanocobalamin, and methionine) were substituted, after which the tetraparesis improved markedly. 

Other more specific routes are employed for the administration of the active substance directly to the therapeutic site. For administration into the central nervous system the intrathecal, epidural or infracistemal injection route is used. Intrathecal injection is an injection into the spinal canal, more specifically into the sub-arachnoid space so that it reaches the cerebrospinal fluid and is useful in spinal anaesthesia, chemotherapy, or pain management applications. This route is also used for antibiotic treatment of infections, particularly post-neurosurgical. Medicines given intrathe-cally must not contain any preservative. 

Scalzone M, Cocda P, Cerdiiara G, Maurizi P, Mastrangelo S, Ruggiero A, et al. Errors involving patients receiving intrathecal chemotherapy. J Chemother 2010 22(2) 83-7. 

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