CNS treatment for acute leukaemias: triple IT regimens used (MTX 12.5 \200\22315mg, cytarabine 30 \200\22350mg and hydrocortisone 15mg). Usually given twice weekly until CSF clear of blasts then weekly to a maximum of 6 total courses. Consider usi ng folinic acid rescue. 699 INTRATHECAL CHEMOTHERAPY Technique \200 Platelet count should be checked prior to procedure. Generally Platelets >50 \227 109/L is recommended but local guidelines may vary. \200 Standard con traindications to lumbar puncture apply; patient might need imaging or fundoscopy prior to procedure. Alternatives will be needed if contraindicated. Cytotoxics should be made up freshly in smallest possible volume in a sterile drugstore. Consider GA only for children. No sedation for adults as patients should be involved in fi nal checking procedure. Fine-bore needles should be used to avoid CSF leakage and post LP headache. Aim to remove the same volume of CSF as you are injecting intrathecally (may be several mL if giving triple chemotherapy). Take samples for CSF cytospin to determine blast cell concentration, microbiology for MC&S, biochemistry for protein and glucose. Check syringe cytotoxic dose carefully with another person before connecting. Connect syringe and aspirate gently to confi rm position in CSF. Inject slowly, drawing bac k at intervals to reconfi rm position. Disconnect syringe and connect other syringes in tur n if giving \200\230triple \200\231 ITs. In triple IT, the hydrocortisone should be given last. \200 Follow standard post-LP preca utions. Flat bedrest 30 \200\22360min and adequate fl uid intake. Document procedure in notes. Repeated IT chemotherapy carries risk of CSF leakage and post-LP headache. Manometry pre-injection may help assess whether less CSF should be withdrawn pre- injection. Symptoms of MTX-induced neurotoxicity occur in a low number of patients. Presents with feat ures of meningo-encephalitis. Etiology is unknown. Treat with short pulse of high-dose ster oids. Do not give further IT MTX to these patients. 700 CHAPTER 15 Protocols and procedures Management of extravasation Inappropriate or accidental administration of chemotherapy into SC tissue rather than into the IV compartment. Causes pain, erythema, and infl ammation wh ich may lead to sloughing of the skin and severe tissue necrosis. Appropriate early treatme nt can prevent the most serious consequences of extravasation. All chemotherapy units shoul d have a protocol with which all staff administering chemotherapy are familiar. A checked/r egularly updated extravasation kit for the management of extravasation giving fi rst aid in structions and further directions should be readily available. The risk of tissue damage relates to the drug \200\231s ability to bind to DNA, to kill rep licating cells, to cause tissue or vascular dilatation and its pH, osmolarity, concentratio n, volume and formulation components, e.g. alcohol, polyethylene glycol. Cytotoxic drugs are classifi ed into 5 groups by their potential to cause serious necrosis when extravasated. Group 1: neutrals Alemtuzumab; asparaginase; bevacizumab; bortezomib; bleomycin; cetuximab; cladribine; cyclophosphamide; cytarabine; eribulin; fl udara- bine; gemcitabine; ifosfamid e; ipilimumab; melphalan; pemetrexed; pen- tostatin; rituximab; thiotepa; beta-interferons; trastuzumab. Group 2: in \202 ammitants Raltitrexed; fl uorouracil; methotrexate. Group 3: irritants (cause local in \202 ammation, pain, and necrosis) Bendamustine; carbop latin; etoposide; irinotecan; dexrazoxane. Group 4: exfoliants Cisplatin; liposomal daunorubicin; docetaxel; liposomal doxorubicin; mi toxantrone; oxaliplatin; topotecan. Group 5: vesicants Amsacrine; carmustine; dacarbazine; dactinomycin; daunorubicin; doxo- rubicin; epirubicin; idarubicin; mitomycin; paclitaxel; s treptozocin; treo- sulfan; vinblastine; vincristine; vindesine; vinorelbine; vinfl unine. Symptoms and signs \200 Burning, stinging, or pain at the injection site. \200 Indurati on, swelling, venous discolouration/erythema at the site. \200 No blood return from the c annula. \200 Reduced fl ow rate. \200 i resistance to administration. \200 Severe phl ebitis and/or local hypersensitivity. \200 Local risk factors, e.g. diffi cult cannulatio n and one patient symptom. 701 MANAGEMENT OF EXTRAVASATION General treatment guidelines \200 Stop the injection/infusion immediately. \200 Disconn ect the infusion/syringe. \200 Withdraw as much of the drug as possible (via existing can nula or central venous access device). Mark area of skin with indelible pen and if possible take a photograph of the area as soon as possible. If appropriate, remove the peripheral cannula. Leave central lines in place. Establish whether a hot pack or cold pack should be used; for neutral drugs neither is required. In case of a large volume (depending on size and age of patient as well as the drug involve d) extravasation of a vesicant or exfoliant, urgent saline fl ush-out of the extravasation area should be always be considered (best within 2h; no later than 24h after extravasation) . For anthracycline extravasation, the fl ush-out technique should not be used in combinati on with dexrazoxane. Cytotoxics requiring warm pack: inject 1500IU hyaluronidase (in 1mL WFI) via pin-cushion SC injections in 0.1 \200\2230.2mL volumes around the site; apply a warm pack to aid the abso rption of hyaluronidase (warm pack to remain in situ for 2 \200\2234h). Cytotoxics requiring cold pack, either: Cold pack + hydrocortisone cream. Apply cold pack for 15 \200\22320min 3 \200\2234 times a day for up to 3d. Apply hydrocortisone 1% cream tds, as long as redness persists. Or Cold pack + DMSO (98% dimethyl sulfoxide): apply within 10 \200\22325min of the extravasation occurring. Contact with normal skin should be minimiz ed. Once DMSO dries, apply 1% hydrocortisone cream and 30min of cold compression. Repeat pr ocess every 2h for 24h then reduce frequency. Or Consider dexrazoxane if extravasation of doxorubicin, idarubicin, epirubicin or daunorubici n occurs of \211 5mL peripherally or any volume centrally; do not use DMSO in conjunction. Dexrazoxane is a DNA topoisomerase II drug that protects against tissue damage with certai n anthracyclines. Side eff ects include nausea (very common) and neutropenia/thrombocytopen ia (common). Elevate the limb if possible. \200 Manage the situation symptomatically: analgesia as req uired. \200 Appropriate follow-up should be organized. \200 In some cases review by pla stic surgery team recommended. \200 Document the incident in the patient \200\231s notes. 702 CHAPTER 15 Protocols and procedures Speci \201 c procedures after extravasation of cytotoxics commonly used in hematology See Table 15.1. Table 15.1 Immediate treatment required per cytotoxic drug. Drug Cold/warm pack Treatment Amsacrine Cold Hydrocortisone cream Bendamustine Cold Hydrocortisone cream Bleomycin None No antidote Bortezomib None No antidote Carbazitaxel Warm Hyaluronidase Carboplatin Cold Hydrocortisone cream Carmustine Cold Hydrocortisone cream Cisplatin Cold Hydrocortisone cream Cladribine None No antidote Cyclophosphamide None No antidote Cytarabine None No antidote Dacarbazine Cold Hydrocortisone cream Dactinomycin Cold DMSO Daunorubicin Cold DMSO, consider dexrazoxane Docetaxel Warm Hyaluronidase Doxorubicin Cold DMSO, consider dexrazoxane Epirubicin Cold DMSO, consider dexrazoxane Eribulin None No antidote Etoposide Cold Hydrocortisone cream Fludarabine None No antidote Fluorouracil Cold Hydrocortisone cream Gemcitabine None No antidote Idarubicin Cold DMSO, consider dexrazoxane Ifosfamide None No antidote Irinotecan Cold Hydrocortisone cream Liposomal daunorubicin Cold DMSO (for 10 \200\22314d) Liposomal doxorubicin Cold DMSO (for 10 \200\22314d) Melphalan None No antidote Methotrexate Cold Hydrocortisone cream (continued) 703 SPECIFIC PROCEDURES FOLLOWING EXTRAVASATION Table 15.1 (continued) Immediate treatment required per cytotoxic drug. Mitomycin Cold DMSO Mitoxantrone Cold DMSO Oxaliplatin Warm Hyaluronidase Paclitaxel Warm Hyaluronidase Pemetrexed None No antidote Pentostatin None No antidote Raltitrexed Cold Hydrocortisone cream Streptozocin Cold Hydrocortisone cream Topotecan Cold Hydrocortisone cream Treosulfan Cold Hydrocortisone cream Vinblastine Warm Hyaluronidase Vincristine Warm Hyaluronidase Vindesine Warm Hyaluronidase Vinfl unine Warm Hyaluronidase Vinorelbine Warm Hyaluronidase Further reading Allwood, M., et al. (2002). Cytotoxics Handbook, 4th ed. Oxford: Radcliff e Medical Press. Dougherty, L. and Lister, S. (2011). The Royal Marsden Hospital Manual of C linical Nursing Procedures, 8th ed. London: Wiley-Blackwell. European Oncology Nursing Soci ety (EONS) (2007). Extravasation Guidelines 2007. Brussels: EONS. M www.cancerworld.org/Can cerWorld/moduleStaticPage.aspx?id=3891&id_sito=2&id_ stato=1 Gault, D.T. (1993). Extravasat ion injuries. Br J Plast Surg, 46, 91 \200\2236. Mouridsen, H. et al. (2007). Treatment of anthracycline extravasation with Savene (dexrazoxane): results from two prospective clinica l multicentre studies. Ann Oncol, 18, 546 \200\22350. The National Extravasation Informatio n Service. (n.d.). Protocol for Management of Chemotherapy Extravasations. M www.extravasat ion.org.uk/CEG.htm West Sussex & Hampshire (SWSH) Cancer Network. (2013). Guidelines for Pr evention and Management of Chemotherapy Extravasation. Version 7. Guildford: Royal Surrey C ounty Hospital. 704 CHAPTER 15 Protocols and procedures Anticoagulation therapy: heparin For acute thrombosis DVT/PE start with heparin and warfari n simul- taneously. Essential to confi rm diagnosis \200\224but start treatment whilst awai ting results of investigations. When warfarin stable \200\224stop heparin. Heparin Main advantage over oral anticoagulation is immediate anticoagulant eff ect and sho rt t1 \201\2042. Two main products: standard UFH, a mixture of polysaccharide chains, mean MW 15,000, t1 \201\2042 1.0 \200\2231.5h, and LMWH, fragments of UFH (mean MW 5000) with lo nger t1 \201\2042 (3 \200\2236h) and greater bioavailability. LMWH has signifi cant advanta ges: 1 daily SC injection, no monitoring, no dose adjustment, low risk of HITT. Heparins ac t by potentiating coagulation inhibitor antithrombin resulting in antithrombin and anti-Xa activity. Both UFH and LMWH depend on renal clearance. Therapeutic anticoagulation LMWH: given SC od on basis of weight (see individual products f or dosage). Usually continued for 4 \200\2237d until warfarin eff ect, INR >2.0. Standard IV UFH: initial IV bolus 5000IU in 0.9% saline given over 30min (lower loading dos e for small adult/child). Follow with 15 \200\22325IU/kg/h using a solution of 25,000IU hep arin in 50mL 0.9% saline (= 500IU/mL) and a motorized pump, e.g. for 80kg adult dose is 80 \227 25 = 2000IU/h. Monitor IVI with APTT ratio, aim for ratio of 1.5 \200\2232.5, check 6 h after starting treatment. Adjust dose as shown in Table 15.2. Check APTT ratio 10h after dose change; daily thereafter. Use fresh venous sample \200\224d o not take from line. Continue heparin until INR in therapeutic range for warfarin \200\224 takes 75d; massive ileo-femoral throm- bosis and severe PE may require 7 \200\22310d of hep arin. Contraindications Caution if renal, hepatic impairment, recent surgery, known bleeding diat hesis, severe hypertension. Immediate complications of therapy \200 Bleeding occurs even when APTT ratio within the t herapeutic range but risk i with i APTT ratio. Treatment: stop heparin until APTT ratio <2.5. In life- threatening bleeding use protamine sulfate: 1mg/100IU of heparin given in preceding hour. Thrombocytopenia \200\224mild d platelets common early in heparin therapy; not signifi cant . Severe thrombocytopenia less common (HITT); occurs 6 \200\22310d after therapy begun; may be associated thrombosis. Stop heparin. Give alternative antithrombin drug such as lepirud in or danaparoid. Do not start warfarin until thrombocytopenia resolved. Prophylactic anticoagulation LMWH now used in preference to UFH. LMWH given at low dose SC od. Recommended dose usually greater for orthopedic surgery than general surgery. Continue until patient discharged and mobile. 705 ANTICOAGULATION THERAPY: HEPARIN Moderate/high-risk patients \200\224LMWH given 2h pre-op and once daily (E see BNF for dosa ge). UFH SC 5000IU 2h before surgery and bd until patient is mobile. Medical patients are also at risk of VTE and should be assessed for risk and considered for LMWH prophylaxis. Conclusions The i convenience and proven effi cacy means that for most clinical situ- ation s LMWH will now be preferred to UFH. Table 15.2 Heparin infusion adjustment APTR >5.0 4.1 \200\2235.0 3.1 \200\2234.0 2.5 \200\2233.0 TARGET (1.5 \200\2232.5) <1.2 10.5 \200\2232.5 Dose Stopa d300U/h d100U/h d50U/h No i400U/h ii200U/h d500U/h change a Nil for 0.5 \200\2231.0h; check APTT ratio. Doses and dose adjustments (UFH) should follow local guidelines. Further reading Weitz, J.I. (1997). Low-molecular-weight heparins. N Engl J Med, 337, 688 \200\22398. 706 CHAPTER 15 Protocols and procedures Oral anticoagulation with VKA Warfarin is the drug of choice; few side eff ects, well toler ated. A vitamin K antagonist (VKA), it takes 772h to be eff ective; stable state takes 5 \200\2237d. t1 \201\2042 735h. Circulates mainly bound to albumin; free warfarin is active. Many drugs i warfarin eff ect by displacing it from albumin. Monitored by PT using the int ernational normalized ratio (INR). Administration Given daily. Usually given with heparin on d1. If massive thrombosis, delay warfarin for 2 \200\2233d. Standard adult regimen = 10mg/d for 2d. Load with caution using reduced dose if liver disease, interacting drugs, patient >80 years. Check INR <1.4 before loading. Check INR daily for 1st 4d1 on d3, 716h after 2nd dose, and adjust as follows. Tar get INR usually 2.5 except for mechanical heart valves in mitral posi- tion when target is 3.0 or 3.5. Complications Hemorrhage. Easy bruising common within therapeutic range \200\224is patient on aspirin? Rate of major bleeds 72.7/100 treatment years, i age i INR. Rare side eff ects \200\224alopecia, warfarin-induced skin necrosis, hypersensitivity, purple toe syndrome. See E Warfarin overdose, p.656 for details. Asymptomatic patient \200 INR >5.0: stop warfarin and reduce dose by at least 25%. Check INR within 1 week. INR >8.0: consider oral vitamin K 1 \200\2235mg. Symptomatic patient Moderate bleeding, INR 5.0 \200\2238.0, give vitamin K 1mg slowly IV. I NR >8.0: give vitamin K 1mg and FFP or factor concentrate. Severe bleeding: vitamin K 5mg I V, and concentrate containing factors II, VII, IX, and X (e.g. Beriplex). Observe in hospit al. Vitamin K reverses over-anticoagu- lation in 24h. Look for causes of over-anticoagulati on, e.g. heart failure, alcohol, drugs. Reference 1. Anonymous (1998). Appendix II, Guidelines on oral anticoagulation: third editi on. Brit J Haematol, 101, 374 \200\2238. Further reading Kearon, C. and Hirsh, J. (1997). Management of anticoagulation before and a fter elective surgery. N Engl J Med, 336, 1506 \200\22311. 707 ORAL ANTICOAGULATION WITH NOAC Oral anticoagulation with NOAC Dabigatran etexilate is an oral prodrug which is hydrolysed in the liver to the direct thrombin inhibitor dabigatran. Doses recommended for clinical us e are 150 mg od, 220mg od, 110 mg bd, and 150mg bd. Peak plasma levels are reached 2 \200 \2233h after ingestion. Dabigatran is 80% renally excreted with a t1 \201\2042 of 713h with a GFR of >80 mL/min and 18h with a GFR of 30 \200\22350 mL/min. There is a dose-dependent eff ect of dabigatran on laboratory clotting tests. Rivaroxaban is an oral direct inhibitor of factor Xa. Doses recom- mended for clinical use are 10mg od and 20mg od (15mg bd for fi rst 3 weeks of treatment of DVT). Peak plasma level s are reached 2 \200\2233h after ingestion. Rivaroxaban is 33% renally excreted and in pati ents with normal renal function has a t1 \201\2042 of 9h. There is a dose-dependent eff ect of rivaroxaban on laboratory clotting tests. For both drugs peak plasma concentrations are in the range of 100 \200\223 400ng/mL. Trough concentrations are in the range of 20 \200\223150ng/mL. Urgent assessment of the degree of anticoagulation may be required: \200 Before surgery o r invasive procedure when a patient has taken a drug in the previous 24h (or longer if CrCl <50mL/min). When a patient is bleeding. \200 When a patient has taken an overdose. \200 When a pati ent has developed renal failure. \200 When a patient has thrombosis on treatment (to asse ss whether there is failure of therapy or lack of adherence). The APTT using most reagents can be used for urgent determination of the relative intensity of anticoagulation due to dabigatran. The APTT cannot be used to determine the drug level. A normal TT means the level of dabigatran must be very low. With an appropriate reagent the PT (or APTT) can be used for the urgent determination of th e relative intensity of anticoagulation due to rivaroxaban. The PT is usually more sensitiv e. It cannot be used to determine the drug level. 708 CHAPTER 15 Protocols and procedures Management of needlestick injuries Every doctor dealing with high-risk patients is concerne d to prevent exposure to blood and body fl uids, particularly a needlestick injury. The UK DoH published guidance on post-exposure prophylaxis (PEP) for HIV in 2008.1 Your hospital/G P surgery should have a policy for the pre- vention and management of contamination inciden ts \200\224check this out. Hospitals should have a 24 h service providing advice and treatm ent. Risk to healthcare workers 2 types of injury \200\224sharps injury where intact skin is bre ached by sharp object contaminated with blood/blood-stained body fl uids or unfi xed tissue , and contamination injury where blood/blood-stained body fl uid comes into contact with mu cous membranes or non-intact skin. HBV and HIV are the 2 major concerns. All healthcare wor kers should be vac- cinated against HBV. Risk of contracting HIV from percutaneous expo- su re to HIV-infected blood is 70.3%. The amount of blood injected and a high viral load in th e patient \200\231s blood i the risk. General guidelines Prevention All healthcare workers must adopt universal precautions when han- dling blood/blood stained fl uids \200\224wear gloves, avoid blood spillage, use decon tamination procedures if spillage occurs, label high-risk specimens, care with needles (do not resheath), disposal in burn bins, etc. Immediate action in event of exposure \200 Encourage bleeding and/or wash under running w ater. \200 Contact Occupational Health/Emergency departments for help. \200 Establish p atient status re: blood-borne viruses. \200 Take blood from patient/test for viruses (wit h consent). \200 Take blood from needlestick victim and store. Check HBV immunity/ later tests if necessary. Treatment \200 Decision to treat will be made by an experienced medical staff member. Tre atment recommended for \200\230all healthcare workers exposed to high-risk body fl uids or tissues known to be, or strongly suspected to be, infected with HIV through percutaneous e xposure, mucous membrane exposure or through exposure of broken skin \200\231. Zidovudine a lone given as soon as possible d risk of seroconversion by 80% but failures are well descri bed. Prophylaxis with triple therapy now recommended. Treat for 4 weeks as soon as possible with: \200 Zidovudine 200mg tds/250mg bd + lamivudine 150mg bd + indinavir 800mg tds. A \200\230starter pack \200\231 should be available in an accessible place at all times. \200 Known exposure to hepatitis B: No immunity \200\224give HepB Ig 500mg IM; vaccinate immediately. \200 Known immunity wit h HepB Ab >100IU/L in past 2 years \200\224no action. Immunity \200\224HepB Ab status not known \200\224give booster dose. 709 MANAGEMENT OF NEEDLESTICK INJURIES Reference 1. Department of Health (2008). HIV post-exposure prophylaxis: guidance from the UK Chief Medical Offi cers \200\231 Expert Advisory Group on AIDS. M www.dhsspsni.gov.uk/hss-md-34-2 008- attachment-1.pdf 710 CHAPTER 15 Protocols and procedures Chemotherapy protocols The schedules discussed on E pp.711 \200\223743 are the most frequen tly used chemotherapy regimens. Where available, local guidelines should be followed. Recom mendations on dose reduction, count recovery, and G-CSF use are also aimed at being guidanc e; local advice and guidance should be followed. Diff erent schedules and combinations are in use with geographical diff erences. Protocols covered in the following topics \200 ABVD \200 BEACOPP/escalated BEACOPP \200 BEAM/LEAM \200 Bortezomib/dexamethasone \200 CHOP 21 and CHOP14 \200 ChlVPP \200 CODOX-M/IVAC R \200 CTD/CTDa \200 DHAP R \200 ESHAP R \200 FC R \200 ICE R \200 Lenalidomide/dexamethasone \200 MPT \200 Mini-BEAM R \200 No rdic schedule (R-maxi-CHOP and R-high-dose cytarabine for MCL) PMitCEBO \200 R-Bendamustine \200 R-CHOP \200 R-CVP and CVP \200 Rituximab: monothe rapy and maintenance therapy \200 Stanford V. 711 ABVD ABVD Indication HL (1st line). Schedule 28d cycle (Table 15.3). Table 15.3 ABVD Days Drug Dose Route 25mg/m2 10,000IU/m2 6mg/m2 IV (max. l0mg) 1 & 15 Doxorubicin Bleomycina IV bolus IVI in 500mL 0.9% saline 1 & 15 IVI in 50mL 0.9% 1 & 15 Vinblastine 375mg/m2 IVI in 250mL 0.9% saline over at least 60min. Saline over 5 \200\22310min 1 & 15 Dacarbazine a Administer 100mg hydrocortisone IV before bleomycin when dexamethasone not used as an ant iemetic. Administration \200 Out-patient regimen. \200 Aim to give treatment on time irrespectiv e of neutrophil count. Avoid G-CSF unless clinically indicated. Consider sperm banking or egg-harvesting. \200 Add allopurinol 300mg/d (100mg/d if creati nine clearance <20mL/ min) for 1st cycle. Antiemetic therapy for highly emetogenic regimens. \200 In patients with hepatic dysfunct ion, reduce doxorubicin and vinblastine to 50% dose for bilirubin 1.7 \200\2232.5 \227 ULN and reduce to 25% dose for bilirubin 2.5 \200\2234 \227 ULN. Number of treatments dependent on staging (2 \200\2238 cycles). \200 Addition of involved fi eld radiotherapy (IFRT) depending on staging and bulk of disease. Main toxicities: myelosuppression; alopecia; mucositis; pulmonary toxicity; cardiomyopathy; peripheral neuropathy; constipation; skin reactions to bleomycin; rigors during bleomycin infusion; vein pain during dacarbazine infusion; ovarian failure; infertility. 712 CHAPTER 15 Protocols and procedures BEACOPP/escalated BEACOPP Indication HL (advanced stage, refractory/relapsed). Schedule 21d cycle (Table 15.4). Table 15.4 BEACOPP and escalated BEACOPP Days Drug Standard dose Escalated dose 25mg/m2 IV bolus 650mg/m2 IVI 100mg/m2/d IVI 35mg/m2 IV bolus 1250mg/m2 IVI 200mg/m2/d IVI 1 Doxorubicin 1 Cyclophosphamide Etoposidea 1 \200\2233 1 \200\2237 Procarbazine 100mg/d PO 40mg/m2/d PO 10,000IU/m2 IVI 1.4mg/m2 IVI in 50mL 0.9% saline (max. 2mg) 100mg/d PO 40mg/m2/d PO 10,000IU/m2 IVI 1.4mg/m2 IVI in 50mL 0.9% saline (max. 2mg) 1 \200\22314 Prednisolone Bleomycinb 8 8 Vincristine G-CSF Only if necessary Standard 9 until neutrophils >1.0x109/L a Etoposide may be given orally at 200mg/m2. b Administer 100mg hydrocortisone IV before bl eomycin when dexamethasone not used as an antiemetic. Administration \200 Out-patient regimen. \200 Consider sperm banking in or egg-harvesti ng. \200 Add allopurinol 300mg/d (100mg/d if creatinine clearance <20mL/ min) throughout fi rst treatment cycle. Antiemetic therapy for highly emetogenic regimens from d1 \200\2238. \200 Infection proph ylaxis with co-trimoxazole and aciclovir recommended. \200 Reduce bleomycin and etoposide doses to 75% for creatinine clearance 12 \200\22360mL/min and to 50% dose if <12mL/min. Reduce doxorubicin, etoposide and vincristine doses to 50% if bilirubin 1 \200\2232 \227 ULN, to 25% if 2 \200\2234 \227 ULN and omit if >4 \227 ULN. Withhold procarbazine if severe myelosuppression develops. \200 Discontinue procarbazine if paraesthesia, neuropathy, confusion, stomatitis or diarrhea; restart at reduced dose aft er recovery Consider G-CSF support after fi rst episode of febrile neutropenia or delay of treatment \211 1 week. Repeat treatment if neutrophils \211 1.0 \227 109/L and platelets \211 100 \227 109/L. \200 If it is considered essential to continue or delays of 2 \200\2233 weeks fail to achieve adequate recovery, consider dose-reduction. Administer every 3 weeks for 6 \200\2238 cycles. \200 IFRT depending on site and bulk of disease. 713 BEACOPP/ESCALATED BEACOPP 714 CHAPTER 15 Protocols and procedures BEAM/LEAM Indications Myeloablative conditioning regimen for autologous SCT in: \200 Aggressive NHL with chemosensitive relapse or to consolidate remission in poor prognostic disease. HL: refractory or 2nd remission. \200 Indolent NHL refractory to 2nd-line therapy. Schedule Single cycle (Table 15.5). Table 15.5 BEAM and LEAM Days Drug Dose Route 300mg/m2 \210\2227 Carmustine (BCNU) in BEAM IVI in 500mL 5% glucose over 1h; avoid storage in PVC container for >24h 200mg/m2 Lomustine (CCNU) in LEAMa 200mg/m2 bd IVI in 100mL 0.9% saline over 30 min 200mg/m2/d IVI in 1L 0.9% saline over 2h 1 40mg/m2 \210\2226 to \210\2223 (inclusive) Cytarabine \210\2226 to \210\2223 (inclusive) Etoposide Melphalanb \210\2222 IVI in 250mL 0.9% saline within 60min of reconstitution Thaw and reinfuse haematopoietic stem cellsc 0 a Dose as per LACE protocol.1 b Ensure excretion of melphalan by aggressive hydration ( f urosemide). c Ensure stem cell dose \211 2.0 x 106/L CD34+ cells; do not re-infuse stem c ells within 24h of melphalan infusion. 715 BEAM/LEAM Administration \200 In-patient regimen. \200 Ensure adequate venous access by inserting a dual lumen tunneled central venous catheter. Severe myelosuppression is expected (neutrophils <0.1 \227 109/L and platelets <20 \227 109/L). Add allopurinol 300mg (100mg if creatinine clearance <20mL/min) od for 1st week unless remission status confi rmed. \200 Antiemetic therapy for highly em etogenic regimens. \200 Give mouth care (nystatin and chlorhexidine mouthwash) and consider oral systemic antibacterial (e.g. ciprofl oxacin). Give antifungal prophylaxis until neutrophil recovery \211 1.0 \227 109/L \200\224 refer to local protocol for patients with severe neutropenia. Consider H2 antagonist or PPI. \200 G-CSF to start once neutropenic <0.5 \227 109/L unti l count recovery. Consider use of pegylated G-CSF. Consider aciclovir antiviral prophylaxis. \200 Consider Pneumocystis jirovecii prophylaxi s for 6 months after count recovery; refer to local protocol (generally co-trimoxazole 480mg bd tiw). Do not use if creatinine clearance is <40mL/min. \200 Main toxicities: diarrhea, mucositi s, alopecia, myelosuppression infertility. All patients must receive irradiated cellular blood components for at least 12 months post-SCT to prevent transfusion associated GvHD. Reference 1. Perz, J.B. et al. (2007). LACE-conditioned autologous stem cell transplantatio n for relapsed or refractory Hodgkin \200\231s lymphoma. Bone Marrow Transplant, 39, 41 \200\2237. 716 CHAPTER 15 Protocols and procedures Bortezomib/dexamethasone Indications \200 Multiple myeloma. \200 AL amyloid. Schedule 1 21d cycle (Table 15.6). Table 15.6 Bortezomib-dexamethasone Days Drug Dose Route 1.3mg/m2 1, 4, 8, 11 Bortezomib SC 1+2, 4+5, 8+9, 11+12 Dexamethasone 20mg PO Schedule 2 (attenuated) 35d cycle (Table 15.7). Table 15.7 Bortezomib-dexamethasone Days Drug Dose Route 1.3 mg/m2 1, 8, 15, 22 Bortezomib SC 1+2, 8+9, 15+16, 22+23 Dexamethasone 20mg PO Administration \200 Out-patient regimens. \200 Bortezomib now generally given as SC bol us, but can be given IV. \200 Bortezomib containing schedule preferred in patients with r enal impairment. Schedule 2 preferred for patients >70 years old or patients with comorbidities. Weekly cyclophosphamide 500mg PO can be added to both schedules. Add allopurinol 300mg od PO (100mg if signifi cant renal impairment) for fi rst cycle. Antiemetic therapy for mildly emetogenic regimens. \200 Give 4 \200\2238 cycles (to maxim um response plus 2 cycles). \200 Consider a dose reduction of bortezomib if CrCl <20mL/mi n. \200 Hepatic impairment: use bortezomib with caution in mild to moderate hepatic impairment and consider a dose reduction \200\224 clearance is mainly via hepatic metabolism. Contraindicated in severe hepatic impairment. If bilirubin >1.5 \227 U LN, reduce bortezomib to 0.7 mg/m2 in the 1st treatment cycle. Consider dose escalation to 1.0 mg/m2, or further dose reduction to 0.5 mg/m2, in subsequent cycles based on patient to lerability. 717 BORTEZOMIB/DEXAMETHASONE Main toxicities: myelosuppression (thrombocytopenia common but recovers rapidly; neutropeni a usually less severe); postural hypotension; rash; GI toxicity; peripheral neuropathy; exa cerbation/ development of heart failure; steroid side eff ects; injection site reactions; h aemorrhagic cystitis, if cyclophosphamide included. 718 CHAPTER 15 Protocols and procedures CHOP 21 and CHOP 14 Indications \200 (Aggressive and low-grade) NHL. \200 T-cell lymphoma. \200 Rituximab may be added to either regimen (R-CHOP) for CD20+ NHL. Schedule 21d or 14d cycle (Tables 15.8 and 15.9). Table 15.8 CHOP 21: 21d cycle Days Drug Dose Route 750mg/m2 1 Cyclophosphamide IVI in 250mL 0.9% saline over 30min 1.4mg/m2 (max. 2mga) 50mg/m2 1 Vincristine IVI in 50mL 0.9% saline over 5 \200\22310min IV bolus 1 Doxorubicin 1 \200\2235 Prednisolone 100 mg PO in a.m. with food a Cap vincristine at 1mg for patients aged >70 years Table 15.9 CHOP 14: 14d cycle Days Drug Dose Route 750mg/m2 1 Cyclophosphamide IVI in 250mL 0.9% saline over 30min 1.4mg/m2 (max. 2mga) 50mg/m2 1 Vincristine IVI in 50mL 0.9% saline over 5 \200\22310min IV bolus 1 Doxorubicin 1 \200\2235 Prednisolone 100mg PO in a.m. with food SC from d5 for 5 \200\2237d 4 \200\22313 G-CSF: fi lgrastim or lenograstim 5mcg/kg/d or 263mcg/db a Cap vincristine at 1mg for patients aged >70 years b G-CSF dose dependent on weight. Use 368mcg/d in patients >80kg 719 CHOP 21 AND CHOP 14 Administration \200 Out-patient regimen. \200 Consider sperm banking or egg-harvesting. \200 Add allopurinol 300mg/d (100mg if creatinine clearance <20mL/ min) throughout 1st treatment cycle. Antiemetic therapy for moderately emetogenic regimens. \200 CNS prophylaxis with intrathe cal MTX should be administered for certain patients (see E Chapter 5). Some guidelines use high IPI (4 \200\2235) as indication for IT. For patients with BM, testicular, orbital, par anasal/nasopharyngeal or paraspinal involvement prophylaxis should be considered. In patients with renal impairment, reduce cyclophosphamide dose to 75% for creatinine clear ance 10 \200\22350mL/min and to 50% for clearance <10mL/min. In patients with hepatic dysfunction, reduce doxorubicin dose by 50% for bilirubin 1.5 \200\2233 \227 ULN and to 25% for bilirubin >3 \227 ULN. Repeat treatment when neutrophils \211 1.0 \227109/L and platelets \211 100 \227 109/L. Standard 6 cycles. \200 Etoposide or mitoxantrone have sometimes been used to substitute doxorubicin in patients with previous cardiac disease. \200 Main toxicities: myelosuppres sion; alopecia; mucositis; cardiomyopathy; peripheral neuropathy; constipation; haemorrhagic cystitis; ovarian failure ; infertility; organ failure. Risk of TLS: ensure premedicated with allopurinol or rasburicase and good hydration. Consider 1 or 2 G-CSF prophylaxis. 720 CHAPTER 15 Protocols and procedures ChlVPP Indication HL in elderly patients unfi t for ABVD or other intensive 1st-line treat- ment. Possible salvage treatment in relapse. Schedule 28d cycle (Table 15.10). Table 15.10 ChIVPP Days Drug Dose Route 6mg/m2/d (max. 10mg) 6mg/m2 (max. 10mg) 1 \200\22314 Chlorambucil PO IVI in 50mL 0.9% saline over 5 \200\22310min 1 & 8 Vinblastine 100mg/m2/d (max. 150mg) PO 1 \200\22314 Procarbazine 1 \200\22314 Prednisolone 40mg PO in a.m. with food Administration \200 Out-patient regimen. \200 Consider sperm banking or egg-harvesting. \200 Add allopurinol 300mg/d (100mg if creatinine clearance <20mL/ min) throughout 1st treatment cycle. Antiemetic therapy for moderately emetogenic regimens. \200 Consider H2-antagonist or PPI . \200 Alcohol prohibited with procarbazine; avoid tyramine containing foods. \200 In p atients with renal failure, consider dose reduction of procarbazine if creatinine >180micromol/L. In patients with hepatic dysfunction, reduce vinblastine dose to 50% if bilirubin 26 \200 \22351micromol/L or AST 60 \200\223180IU/L; omit vinblastine if bilirubin >51micromol/L and AST/ALT >180IU/L; consider dose reduction of chlorambucil in severe hepatic dysfunction. Repeat treatment cycle when neutrophils >1.0 \227 109/L and platelets >100 \227 109/L, otherwise delay 1 week. Main toxicities: myelosuppression; constipation; peripheral neuropathy; stomatitis; alopecia; steroid side eff ects; ovarian failure; infertility. 721 ChlVPP 722 CHAPTER 15 Protocols and procedures CODOX-M/IVAC R Indication Burkitt lymphoma or Burkitt-like (gray-zone) lymphoma. Schedule Administer 2 alternating cycles of each regimen, i.e. A/B/A/B. Start each regimen as soon as possible after regeneration of neutrophils to >1.0 \227 109/L and unsupported p latelets to >75 \227 109/L. In low-risk patients (low IPI) 3 cycles of CODOX-M can be cons idered (Tables 15.11 and 15.12). Table 15.11 Regimen A: CODOX-M Days Drug Dose Route Cyclophosphamide 800mg/m2 1 IVI in 500mL 0.9% saline over 30min 200mg/m2/d IVI in 250mL 0.9% 2 \200\2235 saline over 15min \227 4d 1.5mg/m2 (max. 2mg) 40mg/m2 IV bolus 1 & 8 Vincristine 1 Doxorubicin IVI in 50mL 0.9% Saline over 5 \200\22310min Cytarabine a MTX b 70mg 300mg/m2 IT injection 1 & 3 IVI in 250mL 0.9% saline over 60min 10 2700mg/m2 15mg/m2 IVI in 1L 0.9% saline over 23h Calcium folinate c 11 IV 36 h after start of MTX; repeat 3hrly for 12 h then 15mg/m2 IV/PO 6hrly until serum MTX level <5 \227 10 \210\2228 M G-CSF (fi lgrastim or lenograstim) 5mcg/kg/d or 263mcg/d* SC 13 until neutrophils >1.0 \227 109/L MTXa Calcium folinatea 15 12mg IT injection 15mg PO 24h after IT MTX 16 a In patients with CNS involvement at diagnosis, intensifi ed CNS therapy is required durin g the fi rst 2 cycles: cytarabine 70mg IT on d1, 3, & 5; MTX 12.5mg IT on d15 & 17; calcium folinate 15mg on d16 & 18. b MTX should only be given if creatinine clearance >50mL/min/m2 . UK trials have used a lower dose of MTX than the original published regimen. Reduce MTX d ose in patients aged >65 years (d10: 100mg/m2 IVI over 60min then 900mg/m2 IVI over 23h). A lkalinize urine to pH \211 7 with 3L/m2 IV fl uids plus NaHCO3 from 24h prior to start of MTX until serum MTX level <5 x 10 \210\2228 M (i.e. until calcium folinate no longer requir ed). Check serum MTX levels every 24h from 48h after start of MTX infusion. c If 48h serum MTX level >2 \22710 \210\2226 M (2.0micromols/L) dose of calcium folinate should be double d. Calcium folinate may be administered PO after 24h of IV administration if patient not vo miting. Consider higher dose of G-CSF if >80kg (368 mcg/d). 723 CODOX-M/IVAC R Table 15.12 Regimen B: IVAC Days Drug Dose Route 60mg/m2/d 1 \200\2235 Etoposide IVI in 500mL 0.9% saline over 60min Mesna a 300mg/m2/d 1 \200\2235 IV bolus or IVI over 15min immediately before ifosfamide 1500mg/m2/d IVI mixed with ifosfam ide in 500mL 0.9% saline over 60min 900mg/m2/d IVI in 500mL 0.9% saline over 12h Ifosfamide b 1500mg/m2/d IVI over 60min mixed with 1 \200\2235 Mesna in 500mL 0.9% saline Cytarabine c 2g/m2 every 12h (4 doses) IVI in 1L 0.9% saline over 3h 1 & 2 MTX d 12mg IT injection 5 Calcium folinated 6 15mg PO 24h after IT MTX G-CSF (fi lgrastim or lenograstim) 5mcg/kg/d or 263mcg/de SC 7 until neutrophils >1.0 \227 109/L a In patients aged >65 years, reduce mesna doses to 200mg/m2 IVI over 15min, 100mg/m2 over 60min with ifosfamide & 600mg/m2 over 12h. b In patients aged >65 years, reduce ifosfamide dose to 1000mg/m2 IVI over 60min. c Add prednisolone 0.5% eye drops tds for 5 \200\2237d du ring & after cytarabine. In patients aged >65 years, reduce cytarabine dose to 1g/m2 IVI ov er 3h every 12h (total 4 doses). d In patients with CNS involvement at diagnosis, intensifi ed CNS therapy is required during the fi rst two cycles: MTX 12.5mg IT on d5; calcium foli nate 15mg PO on d6; cytarabine 70mg IT on d7 & 9. e Consider higher dose of G-CSF if >80kg (368 mcg/d). 724 CHAPTER 15 Protocols and procedures Administration \200 Very intensive in-patient regimen; insert tunneled central venous catheter if possible. Discuss risk of infertility and consider sperm storage. Often no time for egg harvesting due to clinical urgency of treatment. Check creatinine clearance before high-dose MTX. \200 High risk of TLS; start IV hydratio n with \211 4.5 L/m2/d with furosemide PRN to maintain urine output. Commence rasburicase (0.2mg/kg for 5 \200\2237d) or allopurinol 300mg/d. \200 Consider an tibiotic and antiviral prophylaxis. \200 Antifungal prophylaxis. \200 Prophylactic PPI, omeprazole 20mg od or equivalent. \200 CODOX-M highly emetogenic on d1, use 5-HT3 antago nist plus metoclopramide 10mg qds or domperidone 20mg qds for 2d or cyclizine 50mg tds IV/ SC continuous infusion 150mg/d. IVAC d1 \200\2235 very highly emetogenic, use 5-HT3 antagonist plus dexamethasone 8mg bd plus metoclopramide or domperidone or cyclizine. Main toxicities: myelosuppression; alopecia; mucositis; cardiomyopathy; peripheral neuropathy; constipation; organ failure; ovarian failure; infert ility. Some centers add rituximab 375mg/m2 to each cycle. 725 CODOX-M/IVAC R 726 CHAPTER 15 Protocols and procedures CTD and CTDa Indications \200 Multiple myeloma. \200 AL amyloid. CTD schedule 21d cycle (Table 15.13). Table 15.13 CTD Days Drug Dose Route 1, 8, 15 Cyclophosphamide 500mg/d PO PO 1 \200\22321 Thalidomide 50mg/d for 3 weeks then 100mg/d for 3 weeks then 200mg/d 1 \200\2234 & 15-18 Dexamethasonea 40mg/d PO a Reduce d1 \200\2234 only from cycle 4 onwards. CTDa (attenuated) schedule 28d cycle (Table 15.14). Table 15.14 CTDa Days Drug Dose Route 1, 8, 15, 22 Cyclophosphamide 500mg/d PO PO 1 \200\22321 Thalidomide 50mg/d for 4 weeks increasing by 50mg/d every 4 weeks to 200mg/d 1 \200\2234 & 15 \200\22318 Dexamethasonea 20mg/d (alternative: 20 \200\22340mg weekly on d1, 8, 15, 22) PO a Reduce d1 \200\2234 only from cycle 4 onwards. Administration \200 Out-patient regimens. \200 CTDa in elderly patients with co-morbidi ties. \200 Women of childbearing potential must have negative pregnancy test within 24h before starting thalidomide; All patients should be enrolled in a pregnancy-prevention program. Add allopurinol 300mg od PO (100mg if signifi cant renal impairment) for 1st cycle. Consider VTE prophylaxis: add aspirin (75mg/d) for patients at