Antifungal prophylaxis: a systemic azole compound is most routinely used. Fluconazole is in ferior to itraconazole liquid. Posaconazole has been shown to be superior to both and is be coming more commonly used. Local guidelines should be followed. Antiviral prophylaxis: aciclovir is the most useful drug at preventing viral infection (mai nly herpes reactivation). Generally 400mg BD is recommended throughout prolonged phases of neutropenia. Local guidelines should be followed. Additional prophylaxis for speci \201 c situations: history of, or radiological evidence o f, tuberculosis (TB). Consideration should be given to standard anti-TB prophylaxis, e.g. i soniazid for 6 months particularly if prolonged neutropenia is expected. Splenectomized pat ient \200\224 at i risk from encapsulated organisms particularly Streptococcus pneumoniae, Haemophilus infl uenza, and Neisseria meningitidis. Use phenoxymethylpenicillin 500mg od PO or erythromycin 250 mg bd PO if penicillin allergic as prophylaxis switching to high dose amoxicillin/cefotaxime if febrile. 681 PROPHYLACTIC REGIMEN FOR NEUTROPENIC PATIENTS 682 CHAPTER 15 Protocols and procedures Guidelines for use of IV antibiotics in neutropenic patients Urgent/immediate action required if neutropenic patient develops: \200 Single fever spike >38 C. \200 2 fever spikes >37.5 C 1h apart. \200 Symptoms or signs of sepsis or inf ection without fever (e.g. hypotension and tachycardia). Assessment \200 Search for localizing symptoms or signs of infection. \200 Full clinica l examination noting BP, pulse, RR, and oxygen saturations. Examination including oral exam ination, chest, perineum, line sites, skin, and fundi. O2 saturation (pulse oximetry). \200 FBC, U&E, creatinine, LFTs, CRP, PT, APTT, fi brinog en. \200 Perform a septic screen: Blood cultures (10mL per bottle optimizes organism recovery) if central line present, take paired peripheral and central samples. Single further blood culture set if non-response at 48 \200\22372h or condition changes. Repeat cultures every 24h if ongoing fever. Swab relevant sites: wounds, central line exit site, throat. \200 Sputum culture. \200 MSU. \200 Feces if symptomatic incl. C. diffi cile toxin. \200 Viral serology if clinic ally relevant. \200 CXR. \200 Other imaging as relevant, consider sinus CT. \200 Cons ider bronchoalveolar lavage if chest infi ltrates present. \200 Consider risk of invasive fungal infection: HRCT chest if high risk and unresponsive to antibiotics. Empirical treatment Start IV broad-spectrum antibiotics to provide adequate cover. Stop pro phylactic ciprofl oxacin. Local protocols are based on local experi- ence and epidemiology of infections and organism. Follow local protocol where available. One possible protocol is shown here: 1st line: piperacillin-tazobactam 4.5g tds plus gentamicin 5 \200\2237mg/kg OD. If patient has history of penicillin allergy use ceftazidime 2g tds instead of piperacillin-tazobactam . If suspected line infection (exit site infl ammation, symptoms typically after line-use) ad d vancomycin 1g bd and consider line removal. If there are signs of perianal sepsis, mucositis or intra-abdominal infec- tion or if C. di ffi cile is suspected add metronidazole 500mg tds IV/oral. \200 Patients on od gentamicin should have pre-dose level checked 24h after 1st dose then twice weekly if satisfactory. 683 GUIDELINES FOR USE OF IV ANTIBIOTICS Patients on vancomycin should have predose levels checked immediately before 3rd or 4th dose (2nd if renal impairment) then twice weekly if satisfact ory. Reassess at 48h If no response to antibiotics and \210\222ve blood cultures: \200 Consid er switching to 2nd-line antibiotics, e.g. meropenem 1g tds vancomycin (if central line in situ). Consider line removal. \200 Further imaging as clinically indicated. Reassess after further 48h If no response to antibiotics and \210\222ve blood cultures: If high risk for invasive fungal infection: Consider starting antifungal therapy if clinica lly suggestive or signs of invasive fungal infection on imaging (e.g. liposomal amphoterici n 3 \200\2235mg/ kg/d, including a 1mg test-dose). Stop prophylactic antifungal. Request HR CT and consider bronchoscopy with bronchio-alveolar lavage (BAL). If low risk for invasive fungal infection: Consider switching antibiotics after microbiolog y advice. Reassess after further 48 \200\22372h \200 Further management empirical and individual. D iscuss with microbiology. Sometimes switching antifungal agent might be indicated. Duration of therapy If fever responds and cultures are \210\222ve, continue anti-infective treatment until apyrexial for 48h or minimum 5d course. If still neutropenic restart proph ylactic anti-infectives. Antifungal therapy should be continued until complete response and neutrophil regeneration; no fi xed duration can be recommended; oral voriconazole or posac onazole can facilitate early discharge during this period. Wherever possible switching to o ral agents as soon as clinically possible is indicated. +ve cultures Antibiotic therapy may be changed on the basis of +ve cultures and sen- sitivi ties at any time. 684 CHAPTER 15 Protocols and procedures Treatment of neutropenic sepsis: source unknown 3 One of the most common haemato-oncologica l emergencies. \200 May be defi ned as the presence of symptoms or signs of infection in a patient with an absolute neutrophil count of <1.0 \227 109/L. In practice, the neutrophi l count is often <0.1 \227 109/L. Similar clinical picture also seen in neutrophil function disorders such as MDS despite n neutrophil numbers. Can occur without pyrexia, especially patients on steroids. \200 In neutropenic patients all new symptoms must be taken seriously and assessed for possible underlying infective cau ses. Known neutropenic patients or patients at risk of neutropenia must have easy and insta nt access to acute care/hospital admission. Immediate action 3 Urgent clinical assessment. See E Septic shock, p.636 for further detail s; summary: \200 Fluid resuscitation. \200 Insert central catheter if not in situ and m onitor CVP. \200 Start O2 by face mask if pulse oximetry shows saturations <95%. \200 P erform full septic screen. \200 Give 1st dose of 1st-line antibiotics immediately. Follow established protocols. Monitor fl uid balance chart/urine output. \200 If BP not restored with appropriate fl ui d resuscitation, consideration should be given to inotropes. If O2 saturations remain low despite 60% O2 delivered by rebreathing mask, consider (non-invasive) ventilation. \200 Discuss with senior colleague and alert I TU. Subsequent actions \200 Amend antibiotics according to culture results. \200 Follow neu tropenic sepsis protocol as outlined on E p.680. \200 Continue antibiotics for a minimum of 5d and often until neutrophil recovery. If cultures show central line to be source of sepsis, remove immediately if patient not responding. Consider central line removal at presentation if lines suspected source. 685 TREATMENT OF NEUTROPENIC SEPSIS: SOURCE UNKNOWN 686 CHAPTER 15 Protocols and procedures Treatment of neutropenic sepsis: source known/suspected Central indwelling catheters Very common. Organisms usually Staph. epidermidis but can be o ther Staph. spp. and even Gram \210\222ve organisms. Line might appear fi ne, but there ma y be erythema/exudate around entry or exit sites of line, ten- derness/erythema over SC tun nel or discomfort over line track. Suspect line if rigors/symptoms in period after line use /fl ush. Blood cultures must be taken from each lumen and peripherally. Add vancomycin 1g b d IV to neutropenic protocol. If no response or clinical deterioration, remove line immedia tely. Perianal or peridontal Common sites of infection in neutropenic patients. Perianal lesions may become secondarily infected if skin broken. Add metronidazole 500mg IV tds to standard therapy. Painful SC abscesses may form and may require surgical incision. Gum disease and l ocalized tooth infec- tions/abscesses are frequently seen. Arrange OPG and dental review as surgical intervention may be required in non-responders. If possible, best delayed until n eutrophil recovery in most cases \200\224then do electively before next course of chemother apy. Atypical organisms Risk group \200 Patients with HIV infection, HCL, or post-SCT are at h igh risk. \200 Mycoplasma and other atypicals are commonly found and usually community acquired (except Legionella); typically occur shortly after return to hospital an d in patients with chronic lung disease. Follow local protocols, e.g. clarithromycin. Pneumocystis jirovecii pneumonia Risk group Lymphoid malignancy on long-term treatment esp. ALL, steroid usage, prolonged neutropenia/immune-suppression, purine analogs, e.g. fl udar abine and cladribine. Treatment High-dose co-trimoxazole IV initially \200\224watch renal function and adjust dos e to creatinine. Consider giving short pulse of steroid 0.5mg/kg at start of treatment. At- risk patients should remain on long-term prophy- laxis until chemo fi nished and lymphocyte count is >1.0 and/or abso- lute CD4 lymphocyte count >500 \227 106/L. Use co-trimoxazole 480mg bd on Monday, Wednesday, and Friday only, provided neutrophil count maintained >1.0 \227 109/L. Otherwise, or in case of allergy, use nebulized pentamidine 300mg every 3 \200 \2234 weeks with preceding nebulized salbu- tamol 2.5mg. 687 TREATMENT OF NEUTROPENIC SEPSIS: SOURCE KNOWN Fungal Risk group Prolonged severe neutropenia, chronic steroid and antibiotic usage, GvHD. Aspergillus and other molds increasingly common with intensive chemotherapy protocols and post-stem cell transplant. Treatment \200 Follow local protocols. AmBisome 3 \200\2235 mg/kg frequently used as 1s t line. Treatment duration decided on an individual basis, but usually at least until neutr ophil recovery. Voriconazole should be used in suspected/proven fungal CNS infections. Caspofungin can be used as an alternative for 1st-line treatment of invasive fungal infections. Switching to oral agents (posaconazole or voriconazole) should be considered as soon as clinically feasible. Viral: CMV Risk group Allogeneic SCT where donor or recipient is CMV +ve. Disease usually d ue to reactivation rather than de novo infection. Apart from pneumo- nitis, may cause graft suppression, gastritis, oesophagitis, weight loss, hepatitis, retinitis, haemorrhagic cyst itis, colitis, and vertigo. Treatment Ganciclovir or foscarnet. Consider switching agent if lack of response. Monitor b y CMV-PCR in PB. Viral: HSV/HZV Risk group SCT patients and patients on prolonged treatment of lymphoid mali g- nancy. Rare causes of lung disease. Treatment High-dose IV aciclovir 5 \200\22310mg/kg tds IV for minimum 10d. Viral: RSV Risk group Post-SCT recipients. Treatment Consider ribavirin nebulizers. TB and atypical mycobacteria Risk group Prolonged T-cell immunosuppression e.g. chronic ste roid or ciclosporin therapy, chronic GvHD, previous history and/or treatment for TB, uncont rolled or newly-diagnosed HIV. Treatment Often diffi cult to diagnose; empirical treatment required with standard triple t herapy. 688 CHAPTER 15 Protocols and procedures Prophylaxis for patients treated with purine analogs The purine analogs fl udarabine and cl adribine used in standard lym- phoproliferative protocols induce neutropenia in all cases. Nadir 714d post-treatment initiation and neutrophil counts may fall to zero for several day s or even weeks. They are associated with the usual neutro- penic infections. In addition, purine analogs have a particular property of inhibition of CD4 helper lymphocy te subsets within weeks of initiation of therapy (nadir at 3 months) and may last for >1 ye ar following cessation of therapy. This profound CD4 function inhibition predisposes to fun gal infection, as well as a higher incidence of HZV infection and P. jirovecii. Reduced lym phocyte function also predisposes to transfusion associated GvHD by passenger lymphocytes i n donor blood transfusions. The following preventive measures are recommended: Recommended \200 Irradiation of all ce llular blood products (2500cGy) from d1 of initiation of therapy and continued until at lea st 2 years post-treatment. P. jirovecii prophylaxis from start of therapy \200\224usually co-trimoxazole 480mg bd Mond ays, Wednesdays, and Fridays. In patients who are allergic or already severely neutropenic, co-trimoxazole may be substituted by pentamidine nebulizers 300mg 4-weekly with 2.5mg of s albutamol nebulizer pre-treatment. P. jirovecii prophylaxis should continue for 3 months af ter the end of treatment. HZV prophylaxis \200\224aciclovir 400mg qds if considered. Most physicians will not wish to have patients continuously on this dosage throughout treatment and for a year post-treatme nt so suggest: counsel patients about the risk of shingles and advise to contact the hospit al immediately if shingles suspected. Aciclovir 400mg BD can be used, but dose below optimu m recommended dose. Optional \200 Antibacterial prophylaxis; consider use of ciprofl oxacin 250mg bd PO from d7 l d21 of each course. Not standard practice. \200 Antifungal prophylaxis: follow local protocol. Fluconazole, itraconazole (liquid), and posaconazole used. 689 PROPHYLAXIS FOR PATIENTS TREATED WITH PURINE analogs 690 CHAPTER 15 Protocols and procedures Tumor lysis syndrome Potentially life-threatening metabolic derangement resulting from trea t- ment-induced or spontaneous tumor necrosis causing renal, cardiac, or neurological compl ications. Usually occurs in rapidly proliferating, highly chemosensitive neoplasms with hig h tumor load: leukaemias with high WBC counts (mainly ALL or AML; rarely CML, CLL, PLL, or ATLL) and high-grade NHL (particularly Burkitt lymphoma or DLBCL). May occur before or up t o 5d (usually 24 \200\22372h) after initiation of chemotherapy. Pathophysiology and clinical features Rapid lysis of large numbers of tumor cells releases intracellular elec- trolytes and metabolites into the circulation causing numerous metaboli c abnormalities to develop rapidly: \200 Hyperuricaemia due to metabolism of nucleic acid purines; (solubility d by high acidity); may cause arthralgia and renal colic. Hyperkalaemia due to rapid cell lysis; often earliest sign of TLS; aggravated by renal failure; may cause paraesthesia, muscle weakness, and arrhythmias. Hyperphosphataemia due to rapid cell lysis; precipitates calcium phosphate in tissues. Hypocalcaemia 2 to hyperphosphataemia; may cause paraesthesia, tetany, carpo-pedal spasm, altered mental state, seizures, and arrhythmias. Acute kidney injury predisposed by volume depletion and pre-existing dysfunction; due to ur ic acid nephropathy, acute nephrocalcinosis, and precipitation of xanthine; oliguria/anuria leads to volume overload and pulmonary oedema; uraemia causes malaise, lethargy, nausea, a norexia, pruritus, and pericarditis; may require dialysis; usually reversible with prompt t herapy. Principles of management \200 Identify high-risk patients, initiate preventative measures prior to chemotherapy, and monitor for clinical and laboratory features of TLS. \200 Detect featur es of TLS promptly and initiate supportive therapy early. \200 Raise/increase staff aware ness of possible TLS. Prevention and management \200 Monitor weight, strict fl uid balance, renal function, ser um K+, phosphate, Ca2+, uric acid, and ECG. Twice daily for fi rst 48h in patients with high clini cal likelihood of TLS. Monitor parameters at least 2 \227 daily in patients with TLS. Ensure aggressive IV hydration: Aim for urine output >100mL/h (>3L/d) from prior to chemotherapy and in high-risk patients, until 48 \200\22372h after initiation of chemothera py. Furosemide (20mg IV) may be given cautiously to maintain adequate diuresis in well-hydrated patients; may be used to treat hyperkalaemia or fluid ov erload but may cause uric acid or Ca2+ deposition in dehydrated patients; no proven benefit in initial treatment of TLS and not routinely given. 691 tumor LYSIS SYNDROME Prevent hyperuricaemia: allopurinol and rasburicase not given together. \200 Allopurinol: xanthine oxidase inhibitor; prevents uric acid formation. \200 Dose: 300 \200\223600mg/d PO for prophylaxis if normal renal function (100mg/d if creatine >100mmol/L). Side eff ects: rash, xanthine urolithiasis; reduce dose in renal impairment or mercaptopurine, 6-thioguanine or azathioprine therapy. Rasburicase: recombinant urate oxidase; converts uric acid to water-soluble metabolites without increasing excretion of xanthine and other purine meta bolites; very rapidly reduces uric acid levels and simplifi es management of high-risk pati ents. Dose 200mcg/kg daily IVI over 30min for up to 5 \200\2237d; recommended in all BL, high count leukemia and as rescue treatment in hyperuricaemia plus r apidly rising creatinine, oliguria, phosphate \211 2mmol/L or K+ \211 5.5mmol/L. Side eff ects: fever, nausea, vomiting; less common: haemolysis, allergic reactions or anaphylaxis; contraindicated in G6PD defi ciency and pregnancy. Alkalinization of urine: Not routinely done; requires close monitoring. \200 Administer NaHCO3 PO (3g every 2h) or IV through central line to i urinary pH to 7.0 and maximize uric acid solubility. Risk of more severe symptoms or hypocalcaemia and i CaPO4 precipitation in tubules. Require s close monitoring of urinary pH (test all urine passed), serum bicarbonate, and uric acid; withdraw IV sodium bicarbonate when serum bicarbonate >30mmol/L, urinary pH >7.5 or serum uric acid normalized. Control of electrolytes: Hyperkalaemia: treat aggressively: \200\223 Restrict dietary K+ intake and eliminate K+ from IV fl uids. \200\223 Use K+ was ting diuretics with caution. \200\223 K+ >5mmol/L, start Ca2+ resonium 15g PO qds and i hydration; recheck K+ after 2h. \200\223 K+ >6mmol/L, check ECG; commence IVI of 50mL 50% dextrose with 20 units of soluble insulin over 1h. \200\223 ECG changes or K+ >6.5mmol/L, give 10mL Ca2+ gluconate 10% or CaCl2 10% IV cardioprotection. Hyperphosphataemia: \200\223 Commence oral phosphate binding agent. \200\223 Infuse 50mL 50% dextrose with 20 units of soluble insulin IV over 1h. Dialysis: Seek renal and critical care consultations early if initial measures fail to control electrolyte abnormalities or renal failure. Dialysis indicated if persisten t hyperkalaemia (>6mmol/L) or hyperphosphataemia (>3mmol/L) despite treatment, fl uid overl oad, rising urea or creatinine, hyperuricaemia (>0.6mmol/L), or symptomatic hypocalcaemia. 692 CHAPTER 15 Protocols and procedures Administration of chemotherapy Cytotoxic chemotherapeutic drugs may cause serious harm if n ot pre- scribed, dispensed, and administered with great care. Drugs should be prescribed, d ispensed, and administered by an experienced multidiscipli- nary team with shared clear inf ormation on: \200 The fi tness of the patient to receive chemotherapy: clinical and based on blood tests (recent FBC and biochemistry). Appropriate protocol and chemotherapeutic regimen for the patient. All treatment should be discussed in a multidisciplinary setting. Prescribed drugs and individualized dosage for the patient \200\231s surface area or weight. Diff erent calculations for BSA exist: most chemotherapy is now pre scribed through an electronic prescribing system, where the BSA is calculated; smart phones apps also used. Safe cumulative maximum doses (e.g. anthracyclines) with safeguarding mechanism to monitor this. Appropriate supportive treatment required, e.g. allopurinol, antiemetic prophylaxis, anti-infective prophylaxis, and hydration. Diff erent for each sche dule. Chemotherapy for IV administration should be reformulated carefully in accordance with the manufacturer \200\231s instructions by an experienced pharmacist using a class B laminar ai rfl ow hood or isolator. Care should be taken to ensure that the drug is administered withi n the expiry time after it has been reformulated in the form chosen. Many cytotoxic drugs are best administered as a slow IVI in glucose or 0.9% saline over 30m in \200\2232h. Vesicants, (e.g. mitoxantrone, daunorubicin) should be administered as a slo w IV \200\230push \200\231. However this should only be administered through the side acce ss port of a freely fl owing infusion of 0.9% saline or dextrose and should never be inject ed directly into a peripheral vein. NB Following a 2008 UK National Patient Safety Agency alert, vinca- alkaloids must be admin istered as a short IV infusion (not in syringe or via IV \200\230push \200\231) to avoid t he risk of inadvertent intrathecal administration. If the patient does not have an indwelling IV catheter (central line, Hickman line, or othe r), an IV cannula of adequate bore should be inserted into a vein to permit a freely fl owi ng 0.9% saline infusion to be commenced. The site chosen should be one where the cannula ca n be easily inserted and observed, can be fastened securely, and will not be subject to mov ement during drug administration. The veins of the forearm are the most suitable for this p urpose followed by those on the dorsum of the hand. The antecubital fossae and other sites close to joints are best avoided. The risk of extravasation is i by the use of a cannula wh ich has not been inserted recently and by the use of steel (butterfl y) cannulae. A slow \200\230push \200\231 injection should be administered carefully into the side acce ss port on the IV line with continuous observation of the drip chamber to ensure that the i nfusion is continuing to run during injection of the cytotoxic drug. The patient should be asked whether any untoward sensations are being experienced at the site of the infusion and the site 693 ADMINISTRATION OF CHEMOTHERAPY should be carefully observed to ensure that no extravasation is occur- ring. Patency of the IV site should be verifi ed regularly throughout the procedure. The administration of potentially extravasable chemotherapy, site of cannulation, condition of the site, and any symptoms associated with administration should be clearly documented in the patient \200\231s notes. Prevention of extravasation \200 Use a peripherally inserted central catheter line or oth er central line for slow infusion of high-risk cytotoxics. Administer cytotoxics through a recently sited cannula located where it cannot be dislodged, e.g. the forearm rather than near joints. \200 Administer vesican ts by slow IV push into the side arm port of a fast-running IV infusion of compatible solution. Administer the most vesicant drug fi rst. \200 Assess a peripheral site continuously for signs of redness or swelling. \200 Verify the patency of the IV site prior to vesicant in fusion and regularly throughout. If in doubt, stop and investigate. Resite if not satisfactory. Advise the patient to report any symptoms of pain, burning, or discomfort at the infusion site. Never hurry. Administer cytotoxics slowly to allow dilution and assessment of the infusion site. 694 CHAPTER 15 Protocols and procedures Antiemetics for chemotherapy Classi \201 cation of antiemetics Dopamine antagonists: block D2 receptors in the chemorec eptor trigger zone (CTZ). Examples are metoclopramide and domperidone \200\224both have add itional eff ects on enhancing gastric emptying. Side eff ects with metoclopramide, include extrapyramidal reactions and occasionally ocu- logyric crisis (younger female patients at m ost risk therefore use dom- peridone). Phenothiazines: examples are prochlorperazine and cyclizine \200\224particular benefi t in opioid-induced nausea. Side eff ects include anticholinergic eff ects and drowsiness. Benzodiazepine: lorazepam most commonly used. Advantages are long t 1 \201\2042 and additio nal anxiolytic eff ect. Side eff ects include drowsiness. 5-HT3 antagonists: block 5-HT3 re ceptors in the CTZ. Examples include ondansetron and granisetron. Side eff ects include hea daches, bowel dis- turbance, and rashes. Cannabinoids: nabilone is the major drug. Side eff ects include deperson- alization experie nces. Steroids: examples are dexamethasone and prednisolone. Side eff ects include predisposition to fungal infection, hypertension, irritability and sleeplessness, gastric erosions and, w ith chronic use, diabetes and oste- oporosis. NK1 receptor antagonists: e.g. aprepitant, used in addition to dexametha- sone and 5-HT3 an tagonist for highly emetic chemotherapy, e.g. high- dose cisplatin. Emesis with chemotherapy Categorized as anticipatory, acute, or delayed. Anticipatory: occurs days to hours in advance of chemotherapy. Psychogenic in origin, it oc curs in patients with previous bad experiences of nausea and vomiting and almost unknown pr ior to 1st dose. May be largely prevented by ensuring a positive experience with 1st dose b y use of prophylactic antiemetics. Acute: occurs <24h, sometimes within minutes of IV chemotherapy or within hours of oral che motherapy. Generally responds best to antiemetics. Delayed: occurs >24h after the end of a chemotherapy course, up to 6 \200\2237d. The most d iffi cult form to treat; requires continuation of anti- emetics throughout post-chemo perio d and even the newer agents such as the 5-HT3 receptor antagonists are relatively ineff ect ive. Antiemetics: may be used singly or in combination and should be admin- istered regular ly, prophylactically and orally. Optimal control in the early phase is essential to prevent nausea and vomiting in the late phase. IV antiemetics are only required if patient is unab le to take oral drugs. Choice of antiemetic is determined largely by patient preferences an d 695 ANTIEMETICS FOR CHEMOTHERAPY degree of emetic potential of the chemotherapy regimen used, classed as high, moderate high , moderately low, and low. Risk factors: female sex, age <30 years, history of sickness in preg- nancy or with travel, prior chemotherapy-induced nausea/vomiting, anxiety. Other factors: radiotherapy, other me dications, metabolic dis- orders, constipation, GI obstruction. If \211 3 factors, conside r additional antiemetic therapy from start of chemotherapy. Grading of nausea and vomiting \200 Grade 1: able to eat; vomiting: 1 episode/24h. \200 Grade 2: oral intake signifi cantly d; vomiting: 2 \200\2235 episodes/24h. \200 Grade 3: no signifi cant intake, requiring IV fl uids; vomiting \211 6 episodes/24h. Grade 4: requiring TPN, or physiological consequences requiring ITU; haemodynamic collapse. High emetic risk Cisplatin \211 50mg/m2, high-dose cyclophosphamide >1.5g/m2, carmus- tine >250mg/m2, dacarbazine, chlormethine (mustine), TBI. Moderately high emetic risk Cisplatin <50mg/m2, daunorubicin, doxorubicin \211 60mg/m2, id arubicin, cytarabine \211 1g/m2, ifosfamide, carboplatin, carmustine \211 250mg/m2, lomus tine. Moderately low emetic risk Doxorubicin <60mg/m2, mitoxantrone, gemcitabine, etoposide, meth otrexate (MTX) 50 \200\223250mg/m2, oral cyclophosphamide, oral procarbazine. Low emetic risk Examples include oral chlorambucil, oral melphalan, oral busulfan, oral hyd roxycarbamide, oral 6-mercaptopurine, vinca-alkaloids, MTX <50mg/m2, fl udarabine, cladribi ne (2-CDA), bleomycin, asparaginase and most steroid-containing protocols. Antiemesis of high and moderately high emetic risk FOLLOW LOCAL GUIDELINES \200 Acute: immediately before chemotherapy: ondansetron 8mg IV p lus dexamethasone 8mg IV plus ondansetron 8mg PO 712h after IV ondansetron dose. Delayed: dexamethasone 2mg tds for 3d, starting the morning after chemotherapy plus domperi done 10 \200\22320mg PO tds regularly for 3d, then PRN. Chemotherapy containing cisplatin >50 \200\22370 mg/m2: as above plus 20 \200\22360min before chemotherapy: aprepitant 125mg PO in acute phase and aprepitant 80m g PO d2 and d3. 696 CHAPTER 15 Protocols and procedures 2nd-line; acute: as for 1st-line, but substitute the single oral dose of ondansetron with o ndansetron 8mg PO + 8h and + 16h after IV ondansetron. Consider need for lorazepam pre-chem otherapy if any anticipatory nausea. 2nd-line; delayed: substitute the single oral dose of ondansetron with: ondansetron 8mg PO every 12h \227 3 doses, starting 12h after IV ondansetron. Increa se the duration of dexamethasone up to 5 \200\2237d. Alternative options include levomeprom azine or cyclizine as a substitute or in addition to domperidone. 2nd-line for grade 3 or 4 nausea/vomiting: consider aprepitant. Aprepitant 125mg PO 20 \200\22360min before chemotherapy starts, followed by aprepitant 80m g PO od on the morning of d2 and d3. Antiemesis of moderately low emetic risk \200 Acute: metoclopramide 10mg IV (or domperido ne 20mg PO tds) plus dexamethasone 8mg IV. Delayed: dexamethasone 2mg tds for 3d starting the morning after chemotherapy plus domperidone 10 \200\22320mg PO tds regularly for 3d, then PRN. 2nd-line: ondansetron and dexamethasone in acute phase. Consider all other alternatives (le vomepromazine, cyclizine in addition to domperidone). Antiemesis of low emetic risk \200 Acute: no routine prophylaxis required for most regime ns. Consider metoclopramide 1 \200\22320mg PO tds/PRN or domperidone 20mg PO tds/PRN. Delayed: consider domperidone 20mg PO tds/PRN if required. \200 2nd-line: dexamethasone 8 mg PO/IV prior to chemotherapy plus domperidone 20mg PO tds/PRN) for 3 \200\2234d. Other situations \200 If severe emesis occurred requiring hospital visit/admission (grade 3 or 4), consider aprepitant. Some schedules have many days of chemotherapy and the antiemetic doses of steroids (dexamet hasone) might be preferred to be avoided (to avoid steroid side eff ects, infections). Cons ider alternative antiemetics in this case. 697 ANTIEMETICS FOR CHEMOTHERAPY 698 CHAPTER 15 Protocols and procedures Intrathecal chemotherapy Administration of IT chemotherapy has to be controlled by strict ( national) guidelines to prevent administration of the wrong chemo- therapy agent intratheca lly. This has happened more than once in the past with catastrophic eff ects. The guideline s used must require all medical staff , nursing staff , and pharmacists involved in the pro cedure to undergo training and annual refresher courses to remain eligible to make, adminis ter, and support the administration of IT chemotherapy; this requires strict compliance wit h all grades of staff who may be involved in IT therapy, checking procedures and administra tion of IT therapy. IV chemotherapy due as part of the same cycle of treatment must be give n on a separate day; IT chemotherapy must be administered in a designated area. Indications \200 Given for both prophylaxis and treatment of CNS disease. \200 May be u sed in addition to other CNS disease strategies such as high- dose IV MTX or craniospinal irradiation. CNS involvement is detected by biopsy, presence of blasts on CSF cytospin and/or abnormalities on MRI or CT. The only drugs used intrathecally are: Methotrexate. \200 Cytarabine (Ara-C). \200 Hydrocortisone. \200 All have strict uppe r dosage limits; follow the protocol. Never use any other cytotoxic drugs for intrathecal injection; fatal con- sequences may ens ue. Keep local anesthetic separate from the drugs to be given intrathecally as syringes cou ld get mixed up. Common protocols \200 CNS prophylaxis for high-grade NHL: MTX 10 \200\22312.5 mg 4 \200 \2236 injections at weekly intervals or every 3 weeks coinciding with cycles of treatment ALL: CNS prophylaxis should strictly follow treatment protocols. \200 CNS prophylaxis for AML: not routinely given anymore as prophylaxis. 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)