review article implications of intrathecal chemotherapy...

Review ArticleImplications of Intrathecal Chemotherapy forAnaesthesiologists A Brief Review

Abhijit Nair

Department of Anaesthesiology Basavatarakam Indo-American Cancer Institute and Research Centre Hyderabad 500034 India

Correspondence should be addressed to Abhijit Nair abhijitnair95gmailcom

Received 20 December 2015 Accepted 14 March 2016

Academic Editor Werner Rabitsch

Copyright copy 2016 Abhijit Nair This is an open access article distributed under the Creative Commons Attribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Intrathecal chemotherapy is routinely prescribed in medical oncology practice either for prophylaxis or for treatment ofleptomeningeal disease due to a primary haematological disease or a metastatic disease due to any other malignancy As thesegroups of patients are coagulopathic either because of the disease per se or due to systemic chemotherapy lumbar puncture inthem is considered challenging and is expected to be performed by an anaesthesiologist because of their expertise in this procedureHowever the challenge is not only in performing the lumbar puncture safely but also in dealing with other issues like explainingand handling complications that can happen either due to the drug injected intrathecally or due to a neurodeficit occurring eitherdue to the underlying coagulopathy or due to the progression of leptomeningeal disease

1 Introduction

Anaesthesiologists are trained in performing lumbar punc-ture (LP) during their postgraduation training programmewith a spinal needle to perform spinal anaesthesia for avariety of surgeries involving lower abdomen and lowerextremities In their routine practice in medical colleges orcorporate hospitals or as freelance anaesthesiologist workingat nursing homes they perform spinal anaesthesia veryfrequentlyTherefore they are considered as experts in lumbarpuncture and are requested to perform lumbar puncturefor various specialities like neurology (CSF analysis CSFpressure monitoring) radiology (myelography) and medicaloncology (intrathecal chemotherapeutic agents) especiallywhen it is difficult for the other speciality physicians toperform

Anaesthesiologists usually oblige the specialists by per-forming a lumbar puncture and injecting the drug intrathe-cally prescribed by them after reviewing the coagulation pro-file (platelet count prothrombin time and activated partialthromboplastin time) and after taking an informed consentLiterature describes life-threatening events happening afterintrathecal chemotherapeutic injections [1] What is difficultto answer is that how much liable the anaesthesiologist

is because they punctured the dura for injecting the drugas requested by a specialist for a diagnostictherapeuticpurpose In the court of law both specialists could be equallyresponsible as one has prescribed (the one who wants lumbarpuncture) and the other one who performed the procedure(the anaesthesiologist) The purpose of this article is tobriefly know about the drugs that are injected intrathecallyin medical oncology to know the possible complicationsafter intrathecal (IT) chemotherapeutic injections and thepossible ways where the anaesthesiologist can avoid a medi-colegal issue We have restricted the discussion to the mostcommonly used drugs which are injected intrathecally inthe practice of medical oncology as a part of chemotherapyregimeMethotrexate cytarabine thiotepa trastuzumab andcorticosteroids are the drugs administered intrathecally forprophylaxis or palliative treatment of meningeal involvementdue to haematological malignancies primary brain malig-nancies or metastatic disease (usually breast malignancies)In practice methotrexate and cytarabine are the drugs fre-quently prescribed for intrathecal administration

(1) MethotrexateMethotrexate is a tetrahydrofolate dehydro-genase inhibitor which prevents tetrahydrofolate formationrequired for thymidylate synthesis which is an essential

Hindawi Publishing CorporationScientificaVolume 2016 Article ID 3759845 5 pageshttpdxdoiorg10115520163759845

2 Scientifica

component of DNA (deoxyribonucleic acid) It has antineo-plastic antimetabolite and immunosuppressive properties[2] IT methotrexate is usually prescribed prophylacticallyin patients with leukemia or lymphoma where there is ahigh risk of central nervous system (CNS) involvementTherapeutically IT injection is done in patients with provenor suspected leptomeningeal carcinomatosis 6 to 15mgmethotrexate is usually injected intrathecally IT methotrex-ate is now preferred over cranial irradiation for prophylaxisand treatment of central nervous system leukemia as radi-ation was associated with secondary malignancies growthretardation and developmental delay in pediatric patients[3]

Complications of intrathecal methotrexate are headacheseizures coma neurodeficit aphasia and cardiovascu-lar compromise The neurotoxicity associated with ITmethotrexate are described as acute subacute and chronic[4] The proposed mechanism of neurotoxicity due toIT methotrexate is mediated by adenosine Methotrexateinhibits dihydrofolate reductase which leads to increasedconcentration of adenosine and homocysteine Adenosineleads to cerebral vasodilatation slows neurotransmitterrelease at presynaptic junction and slows neuronal dischargedue tomodified postsynaptic response Neurotoxicity ismoreoften seen in patientswhere it is administered for treatment ascompared to prophylaxis as in established CNS involvementowing to bulky disease the drug does not spread well leadingto toxic concentration of drug at the surrounding tissue [5]Once detected the management includes supportive careand measures to drain CSF like lumbar puncture systemiccorticosteroids and leucovorin MRI with diffusion usuallyshows restricted contrast diffusion within white matterAminophylline being a competitive antagonist of adenosineis used to treat neurotoxicity mediated by methotrexate at adose of 2ndash5mgkg Carboxypeptidase G2 is an enzyme thatmetabolizes methotrexate when given intravenously to itsinactive metabolites 4-deoxy-4-deamino-N-methyl-pteroicacid and glutamate [6]

(2) Cytarabine Cytarabine is a pyrimidine nucleoside analogwhich inhibits the synthesis of DNA at the S phase of thecell cycle Like methotrexate it has antimetabolite antineo-plastic and immunosuppressive properties [7 8] Intrathecalliposomal cytarabine is indicated for the prophylaxis andtreatment of meningeal leukemia brain tumors (medul-loblastoma meningioma neuro-ectodermal tumors germcell tumors and oligodendroglioma) lymphoma and dis-seminatedmalignancies (breast) [9]The liposomal variant ofcytarabine is prepared in the formof biodegradable lipid baseparticles This alteration prolongs the exposure of cytarabinein the cerebrospinal fluid (CSF) The liposomal formulationis known to exert its effect in CSF for a week in childrenand almost 2 weeks in adults whereas the conventionalcytarabine exerts its effect in CSF for less than 24 hours Therecommended dose of liposomal cytarabine is up to 50mgin adults and 35mg in children [10] Chemical arachnoiditisis a frequently encountered problem with intrathecal lipo-somal arachnoiditis It is characterised by headache backpain fever nausea and vomiting This problem usually is

minimised by administration of systemic dexamethasone[11ndash13] Life-threatening neurotoxicity was noticed by Jab-bour et al when systemic and intrathecal cytarabine hadan overlap in high risk patients Neurotoxicity manifestedas cauda equina syndrome encephalopathy seizures andpseudotumor cerebri [14] Yoon et al reported a case involv-ing diffuse cerebral vasospasm and acute cerebral infarctin a 7-year-old child diagnosed as ALL after intrathecalcytarabine [15] Butto et al reported death in a 56-year-oldfemale patient who was treated with intrathecal cytarabinefor leptomeningeal spread due to breast cancer The patientdeveloped progressive loss of consciousness leading to lossof brain stem function and presented with diffuse cerebraloedema on CT scan due to fulminant chemical ventricu-lomeningitis [16]

(3) TrastuzumabTrastuzumab is amonoclonal IgG1 antibodyusually used to treat metastatic breast carcinoma especiallythe tumors which overexpress HER2neu protein In patientswho develop leptomeningeal metastasis (involvement of piaand arachnoid matter) the usual intravenous dose doesnot help because of poor cerebrospinal penetration Insuch cases intrathecal trastuzumab is advocated along withsystemic trastuzumab [17] The dosing and the duration iscontroversial Intrathecal methotrexate andor cytarabine arealso administered intrathecally along with trastuzumab asdescribed in some case series [18] Trastuzumab was usedintrathecally in combination with another monoclonal anti-body rituximab in patients diagnosed with leptomeningealcarcinomatosis [19]

(4) Thiotepa Thiotepa or NN1015840N10158401015840-triethylenethiophospho-ramide is an alkylating agent with broad spectrum anti-neoplastic activity Intrathecal thiotepa has been used incombination with trastuzumab in patients with breast cancerwith leptomeningeal spread [20 21] Although it is approvedfor intrathecal use in meningeal carcinomatosis thiotepa isnot as popular as compared to methotrexate and cytarabinepossibly because large volume studies are not availabledescribing its use Comte et al publish a retrospective studydescribing survival and prognostic factors in breast cancerpatients presenting with meningeal carcinomatosis who weretreated with intrathecal thiotepaThe authors claimed it to bethe largest retrospective cohort of breast cancer patients inwhom IT thiotepa was used The study involved 66 patientswho received thiotepa as either the first line or the secondline of drug The results of the study revealed that althoughpatients benefitted from its use even when used as a secondline drug the median survival was short [22]

2 Postprocedural Care andObservation of High Risk Injection

Patients in whom dural puncture took several attempts andpatients who came for the procedure after a platelet transfu-sion are the high risk ones Usually these patients are hospi-talized therefore they can be monitoredThe nurse involvedin the care of such patients should be instructed to inform

Scientifica 3

the primary physician or the anaesthesiologist if patientdevelops a new onset lower limb weakness severe headachealtered mentation or seizures A multidisciplinary approachshould be executed in such physicians After examining thepatient thoroughly a neurophysician and a neurosurgeonshould be consulted If necessary relevant imaging like a CTscan or an MRI should be considered to rule out hematomain the neuraxis Such patients should be transferred to anintensive care unit for monitoring

How to Avoid a Lawsuit [23] A simple lumbar puncture ina cancer patient leading to complications described relatedto the medication injected or because of a new onset neu-rodeficit can have serious medicolegal implications if certainsimple basic steps are not followed or casually ignoredWe have described some points that should be addressedseriously when involved in such injections

(1) Informed consent the consent should be preferablywritten with all unexpected problems explained to patientandor familymembers Introduce yourself to the patient andfamily members and tell them why you are involved in themedical management Sometimes when the patient or familymembers get apprehensive by seeing a new doctor around itis better to be introduced by the treating physician

(2) It is better to perform a comprehensive neurologicalexamination and if any neurodeficits are encountered itshould be documented in bold letters Patientfamily mem-bers should be told about it if they are not knowing it prior tothe procedure

(3) Document everything (platelet count attempts takenfor the procedure and size of LP needle) If it is not writtenit is not done that is the dictum

(4) If multiple attempts are made or SDPRDP cover isnot given for a low platelet count follow up the patient inthe ward and document your visit Most of the time the ITinjection is offered on an outpatient basis In such situationmaking a telephone call and enquiring about any neurologicalissues not only keeps the anaesthesiologist informed aboutthe patientrsquos condition but also helps to build a rapport

(5) In case of any adverse event or a complicationappropriate consultation (neurologist neurosurgery) shouldbe asked for and if necessary relevant imaging should beadvised (CT scan MRI)

3 Published Guidelines and their Applicationin Medical Oncology [24ndash26]

Most of the time the medical oncology patients whorequire prophylactic or therapeutic lumbar puncture havea low platelet count due to previous or ongoing systemicchemotherapeutic agents When platelet count is less than20000cusdotmm the patients are transfused with single donorplatelets (SDP) or random donor platelets (RDP) But whenplatelet count is around or more than 50000 but less than75000cusdotmm the patients are not transfused even whenthey have a lumbar puncture planned for IT chemotherapyBut ASRA (American Society of Regional Anesthesia) guide-lines have set a cutoff of a platelet count of 75000cusdotmm

for a safe central neuraxial block so as to avoid a possiblespinalepidural hematoma leading to neurodeficits This iswhere the conflict starts The anaesthesiologist is called forhelp in case of a previously difficult LP or an LP which thistime is difficult to the nonanaesthesiology colleague who hasa platelet count much lower than the cutoff recommendedby ASRA and there is no SDPRDP transfusion given to thispatient The oncologistphysician would have given the ITmedication if the LP was successful Now that it is gettingdifficult how should we proceed

Let us consider another situation The anaesthesiologistin order to help a physician in getting a lumbar punctureobliges and the patient develops a neurodeficit (eg hemi-paresis) Whom should the patient blame Unfortunately wedo not have time to explain the possible complications dueto thrombocytopenia or due to the procedure per se whenwe reach the scene to help a person who was unsuccessful inperforming an LP about We assume or it is quite likely thatthe oncologist must have explained drug related problemsto the patientfamily members (eg neurotoxicity) Thepatientfamily members will not forget the new person whomanaged an LP who is otherwise not seen during his orher treatment In case of a child the parents will noticethat the puncture was done by a different person who is notdirectly involved in the treatment of the patient However insituations where the help of an anaesthesiologist is taken incase of a previously difficult LP there is time to take a properinformed consent and explain possible complications relatedto thrombocytopenia to the patient The anaesthesiologistcan actually request the oncologist for a platelet transfusion(single donor or random donor) and get the LP done underthe cover of the transfusion which is usually done if the countis less than 20000cusdotmm

In case of metastatic leptomeningeal disease the prog-nosis is usually not good There is always a possibility ofsudden new onset neurodeficits due to progressive natureof metastatic disease Patients who have confirmed lep-tomeningeal metastases are usually well counselled by thetreating oncologist However if a lumbar puncture is done insituation with preexisting low platelet count not adequatelycovered by an SDPRDP transfusion it is difficult to provewho is to blame (the disease or the procedure ie LP) incase the patient develops a new onset neurodeficit after theinjection

As a specialist it is difficult to refuse such proceduresbecause an anaesthesiologist is looked upon as an expert indoing LP However evidence based approach and a detaileddiscussion with the oncologist and the patientrsquos family willmake it a hassle-free procedure

4 Use of Ommaya Reservoir forIntraventricular Injection

Ommaya reservoir is an intraventricular catheter systemthat is surgically implanted for either aspiration of cere-brospinal fluid or injecting drugs intrathecally The reservoircan be placed either by an open surgical technique or byusing navigation system [27ndash29] The paper published by

4 Scientifica

Peyrl et al after a 20-year experience with 5472 intraven-tricular drug injections in 98 patients with brain tumorsconfirmed the feasibility and safety of Ommaya reservoirin administering intraventricular injections directly [30]However as expected they suggested to train the personnelinvolved in handling the device with asepsis The reservoirplacement requires general anaesthesia for the patients Byfollowing standard principles of neuroanesthesia that isattenuating hemodynamic response to intubation and extu-bation response avoiding increase in intracranial pressureand avoiding hypertension and hypercarbia the reservoirplacement can be done uneventfullyThe study conducted byZhang showed good outcomes in 45 patients who receivedchemotherapy for intracranial tumors via Ommaya reservoir[31]

5 Conclusion

The anaesthesiologist involved in performing intrathecalchemotherapeutic indications should know the disease ofthe patient the drug which is prescribed for chemotherapyand the possible adverse events associated with the use ofthose drugs A preanaesthesia evaluation should be insistedbefore such procedures and the details of disease previouschemotherapy haematological investigations and neurod-eficits (if any) should be documented Informed consentshould be taken from patient or family member in caseof a minor patient and possible complications should beexplained in detail These injections are electively donetherefore even if an anaesthesiologist spends 15 minutes inspeaking to the patient or family member a rapport canbe developed with them Documentation of the proceduredetails should be always done

Competing Interests

The author declares that there are no competing interests

References

[1] Y-L Kwong D Y M Yeung and J C W Chan ldquoIntrathecalchemotherapy for hematologic malignancies drugs and toxici-tiesrdquo Annals of Hematology vol 88 no 3 pp 193ndash201 2009

[2] A Bay A F Oner O Etlik C Yilmaz and H CaksenldquoMyelopathy due to intrathecal chemotherapy report of sixcasesrdquo Journal of Pediatric HematologyOncology vol 27 no 5pp 270ndash272 2005

[3] B C Widemann F M Balis A Shalabi et al ldquoTreatment ofaccidental intrathecal methotrexate overdose with intrathecalcarboxypeptidase G2rdquo Journal of the National Cancer Institutevol 96 no 20 pp 1557ndash1559 2004

[4] B Malbora E Ozyurek A I Kocum and N Ozbek ldquoDelayedrecognition of intrathecal methotrexate overdoserdquo Journal ofPediatric HematologyOncology vol 31 no 5 pp 352ndash354 2009

[5] R Weigel P Senn J Weis and J K Krauss ldquoSevere compli-cations after intrathecal methotrexate (MTX) for treatment ofprimary central nervous system lymphoma (PCNSL)rdquo ClinicalNeurology and Neurosurgery vol 106 no 2 pp 82ndash87 2004

[6] F Brugnoletti E B Morris F H Laningham et al ldquoRecurrentintrathecal methotrexate induced neurotoxicity in an adoles-cent with acute lymphoblastic leukemia serial clinical andradiologic findingsrdquo Pediatric Blood and Cancer vol 52 no 2pp 293ndash295 2009

[7] A Peyrl R Sauermann F Traunmueller et al ldquoPharmacoki-netics and safety of intrathecal liposomal cytarabine in childrenagedlt3 yearsrdquoClinical Pharmacokinetics vol 48 no 4 pp 266ndash271 2009

[8] A Peyrl R Sauermann M Chocholous et al ldquoPharma-cokinetics and toxicity of intrathecal liposomal cytarabine inchildren and adolescents following age adapted dosingrdquoClinicalPharmacokinetics vol 53 no 2 pp 165ndash173 2014

[9] M Benesch N Siegler K V Hoff et al ldquoSafety and toxicityof intrathecal liposomal cytarabine (Depocyte) in children andadolescents with recurrent or refractory brain tumors a multi-institutional retrospective studyrdquoAnti-CancerDrugs vol 20 no9 pp 794ndash799 2009

[10] D Bhojwani and C-H Pui ldquoIntrathecal liposomal cytarabinemore friend than foerdquo Leukemia amp Lymphoma vol 49 no 8pp 1427ndash1430 2008

[11] R Thienprayoon K M Heym L Pelfrey and D C BowersldquoAccidental overdose of intrathecal cytarabine in childrenrdquoAnnals of Pharmacotherapy vol 47 no 5 article e24 2013

[12] J Gallego Perez-Larraya J A Palma M Carmona-Iragui et alldquoNeurologic complications of intrathecal liposomal cytarabineadministered prophylactically to patients with non-Hodgkinlymphomardquo Journal of Neuro-Oncology vol 103 no 3 pp 603ndash609 2011

[13] R Parasole F Petruzziello C Messina et al ldquoToxicity andefficacy of intrathecal liposomal cytarabine in children withleukemialymphoma relapsing in the central nervous system aretrospective multicenter studyrdquo Leukemia and Lymphoma vol56 no 3 pp 650ndash655 2015

[14] E Jabbour S OrsquoBrien H Kantarjian et al ldquoNeurologic compli-cations associated with intrathecal liposomal cytarabine givenprophylactically in combination with high-dose methotrexateand cytarabine to patients with acute lymphocytic leukemiardquoBlood vol 109 no 8 pp 3214ndash3218 2007

[15] J H Yoon J Y Yoon H J Park et al ldquoDiffuse cerebralvasospasmwith infarct after intrathecal cytarabine in childhoodleukemiardquo Pediatrics International vol 56 no 6 pp 921ndash9242014

[16] A Butto W N Al-Holou L Junck O Sagher and J JFletcher ldquoFulminant chemical ventriculomeningitis followingintrathecal liposomal cytarabine administrationrdquo Journal ofClinical Neuroscience vol 18 no 10 pp 1417ndash1418 2011

[17] C Dumitrescu and D Lossignol ldquoIntrathecal trastuzumabtreatment of the neoplastic meningitis due to breast cancera case report and review of the literaturerdquo Case Reports inOncologicalMedicine vol 2013 Article ID 154674 5 pages 2013

[18] MMego Z Sycova-Mila J Obertova et al ldquoIntrathecal admin-istration of trastuzumab with cytarabine and methotrexate inbreast cancer patients with leptomeningeal carcinomatosisrdquoBreast vol 20 no 5 pp 478ndash480 2011

[19] A J Perissinotti and D J Reeves ldquoRole of intrathecal ritux-imab and trastuzumab in the management of leptomeningealcarcinomatosisrdquo Annals of Pharmacotherapy vol 44 no 10 pp1633ndash1640 2010

Scientifica 5

[20] C Ferrario A Davidson N Bouganim R Aloyz and LC Panasci ldquoIntrathecal trastuzumab and thiotepa for lep-tomeningeal spread of breast cancerrdquo Annals of Oncology vol20 no 4 pp 792ndash795 2009

[21] M J V Maanen C J M Smeets and J H BeijnenldquoChemistry pharmacology and pharmacokinetics of NNrsquoNrdquo-triethylenethiophosphoramide (ThioTEPA)rdquoCancer TreatmentReviews vol 26 no 4 pp 257ndash268 2000

[22] A Comte W Jdid M N Guilhaume et al ldquoSurvival ofbreast cancer patients withmeningeal carcinomatosis treated byintrathecal thiotepardquo Journal of Neuro-Oncology vol 115 no 3pp 445ndash452 2013

[23] R Tabbarah S Tabbarah and G E Kanazi ldquoMedico-legalaspects in anesthesia how to lead a happy liferdquo Middle EastJournal of Anesthesiology vol 18 no 5 pp 985ndash994 2006

[24] J J van Veen T J Nokes and M Makris ldquoThe risk ofspinal haematoma following neuraxial anaesthesia or lumbarpuncture in thrombocytopenic individualsrdquo British Journal ofHaematology vol 148 no 1 pp 15ndash25 2010

[25] T T Horlocker D J Wedel J C Rowlingson et al ldquoRegionalanesthesia in the patient receiving antithrombotic or throm-bolytic therapy American Society of Regional Anesthesia andPain Medicine Evidence-Based Guidelines (Third Edition)rdquoRegional Anesthesia amp Pain Medicine vol 35 no 1 pp 64ndash1012010

[26] Association of Anaesthetists of Great Britain and IrelandObstetric Anaesthetistsrsquo Association and Regional AnaesthesiaUK ldquoRegional anaesthesia and patients with abnormalities ofcoagulationrdquo Anaesthesia vol 68 no 9 pp 966ndash972 2013

[27] M Takahashi R Yamada Y Tabei O Nakamura and NShinoura ldquoNavigation-guided Ommaya reservoir placementimplications for the treatment of leptomeningeal metastasesrdquoMinimally Invasive Neurosurgery vol 50 no 6 pp 340ndash3452007

[28] GMWeiner S Chivukula C-J Chen D Ding J A Engh andN Amankulor ldquoOmmaya reservoir with ventricular catheterplacement for chemotherapy with frameless and pinless elec-tromagnetic surgical neuronavigationrdquo Clinical Neurology andNeurosurgery vol 130 pp 61ndash66 2015

[29] D I Sandberg M H Bilsky M M Souweidane J Bzdil PH Gutin and H S Greenberg ldquoOmmaya reservoirs for thetreatment of leptomeningeal metastasesrdquo Neurosurgery vol 47no 1 pp 49ndash55 2000

[30] A Peyrl M Chocholous A A Azizi et al ldquoSafety of Ommayareservoirs in children with brain tumors a 20-year experiencewith 5472 intraventricular drug administrations in 98 patientsrdquoJournal of Neuro-Oncology vol 120 no 1 pp 139ndash145 2014

[31] J Zhang ldquoTreatment of multiple or recurrent intracranialtumors with local chemotherapy by hypodermic Ommayareservoirrdquo Zhonghua Yi Xue Za Zhi vol 94 no 3 pp 212ndash2142014 (Chinese)

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


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EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

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OphthalmologyJournal of


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Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

2 Scientifica

component of DNA (deoxyribonucleic acid) It has antineo-plastic antimetabolite and immunosuppressive properties[2] IT methotrexate is usually prescribed prophylacticallyin patients with leukemia or lymphoma where there is ahigh risk of central nervous system (CNS) involvementTherapeutically IT injection is done in patients with provenor suspected leptomeningeal carcinomatosis 6 to 15mgmethotrexate is usually injected intrathecally IT methotrex-ate is now preferred over cranial irradiation for prophylaxisand treatment of central nervous system leukemia as radi-ation was associated with secondary malignancies growthretardation and developmental delay in pediatric patients[3]

Complications of intrathecal methotrexate are headacheseizures coma neurodeficit aphasia and cardiovascu-lar compromise The neurotoxicity associated with ITmethotrexate are described as acute subacute and chronic[4] The proposed mechanism of neurotoxicity due toIT methotrexate is mediated by adenosine Methotrexateinhibits dihydrofolate reductase which leads to increasedconcentration of adenosine and homocysteine Adenosineleads to cerebral vasodilatation slows neurotransmitterrelease at presynaptic junction and slows neuronal dischargedue tomodified postsynaptic response Neurotoxicity ismoreoften seen in patientswhere it is administered for treatment ascompared to prophylaxis as in established CNS involvementowing to bulky disease the drug does not spread well leadingto toxic concentration of drug at the surrounding tissue [5]Once detected the management includes supportive careand measures to drain CSF like lumbar puncture systemiccorticosteroids and leucovorin MRI with diffusion usuallyshows restricted contrast diffusion within white matterAminophylline being a competitive antagonist of adenosineis used to treat neurotoxicity mediated by methotrexate at adose of 2ndash5mgkg Carboxypeptidase G2 is an enzyme thatmetabolizes methotrexate when given intravenously to itsinactive metabolites 4-deoxy-4-deamino-N-methyl-pteroicacid and glutamate [6]

(2) Cytarabine Cytarabine is a pyrimidine nucleoside analogwhich inhibits the synthesis of DNA at the S phase of thecell cycle Like methotrexate it has antimetabolite antineo-plastic and immunosuppressive properties [7 8] Intrathecalliposomal cytarabine is indicated for the prophylaxis andtreatment of meningeal leukemia brain tumors (medul-loblastoma meningioma neuro-ectodermal tumors germcell tumors and oligodendroglioma) lymphoma and dis-seminatedmalignancies (breast) [9]The liposomal variant ofcytarabine is prepared in the formof biodegradable lipid baseparticles This alteration prolongs the exposure of cytarabinein the cerebrospinal fluid (CSF) The liposomal formulationis known to exert its effect in CSF for a week in childrenand almost 2 weeks in adults whereas the conventionalcytarabine exerts its effect in CSF for less than 24 hours Therecommended dose of liposomal cytarabine is up to 50mgin adults and 35mg in children [10] Chemical arachnoiditisis a frequently encountered problem with intrathecal lipo-somal arachnoiditis It is characterised by headache backpain fever nausea and vomiting This problem usually is

minimised by administration of systemic dexamethasone[11ndash13] Life-threatening neurotoxicity was noticed by Jab-bour et al when systemic and intrathecal cytarabine hadan overlap in high risk patients Neurotoxicity manifestedas cauda equina syndrome encephalopathy seizures andpseudotumor cerebri [14] Yoon et al reported a case involv-ing diffuse cerebral vasospasm and acute cerebral infarctin a 7-year-old child diagnosed as ALL after intrathecalcytarabine [15] Butto et al reported death in a 56-year-oldfemale patient who was treated with intrathecal cytarabinefor leptomeningeal spread due to breast cancer The patientdeveloped progressive loss of consciousness leading to lossof brain stem function and presented with diffuse cerebraloedema on CT scan due to fulminant chemical ventricu-lomeningitis [16]

(3) TrastuzumabTrastuzumab is amonoclonal IgG1 antibodyusually used to treat metastatic breast carcinoma especiallythe tumors which overexpress HER2neu protein In patientswho develop leptomeningeal metastasis (involvement of piaand arachnoid matter) the usual intravenous dose doesnot help because of poor cerebrospinal penetration Insuch cases intrathecal trastuzumab is advocated along withsystemic trastuzumab [17] The dosing and the duration iscontroversial Intrathecal methotrexate andor cytarabine arealso administered intrathecally along with trastuzumab asdescribed in some case series [18] Trastuzumab was usedintrathecally in combination with another monoclonal anti-body rituximab in patients diagnosed with leptomeningealcarcinomatosis [19]

(4) Thiotepa Thiotepa or NN1015840N10158401015840-triethylenethiophospho-ramide is an alkylating agent with broad spectrum anti-neoplastic activity Intrathecal thiotepa has been used incombination with trastuzumab in patients with breast cancerwith leptomeningeal spread [20 21] Although it is approvedfor intrathecal use in meningeal carcinomatosis thiotepa isnot as popular as compared to methotrexate and cytarabinepossibly because large volume studies are not availabledescribing its use Comte et al publish a retrospective studydescribing survival and prognostic factors in breast cancerpatients presenting with meningeal carcinomatosis who weretreated with intrathecal thiotepaThe authors claimed it to bethe largest retrospective cohort of breast cancer patients inwhom IT thiotepa was used The study involved 66 patientswho received thiotepa as either the first line or the secondline of drug The results of the study revealed that althoughpatients benefitted from its use even when used as a secondline drug the median survival was short [22]

2 Postprocedural Care andObservation of High Risk Injection

Patients in whom dural puncture took several attempts andpatients who came for the procedure after a platelet transfu-sion are the high risk ones Usually these patients are hospi-talized therefore they can be monitoredThe nurse involvedin the care of such patients should be instructed to inform

Scientifica 3
















4 Scientifica


5 Conclusion


Competing Interests


References




















Scientifica 5


















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Scientifica 3
















4 Scientifica


5 Conclusion


Competing Interests


References




















Scientifica 5


















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















4 Scientifica


5 Conclusion


Competing Interests


References




















Scientifica 5


















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Scientifica 5


















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article implications of intrathecal chemotherapy...

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