Special Considerations for the Oncology Patient in the ICU

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1 FSHP 2017 ANNUAL MEETING Disclosure Special Considerations for the Oncology Patient in the ICU I do not have (nor does any immediate family member have) a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially bias my presentation. Ashley Valverde, PharmD, BCPS ANNUAL MEETING 2 Objectives Describe oncology emergencies that may require intensive unit care such as febrile neutropenia, tumor lysis syndrome, hypercalcemia of malignancy and acute promyelocytic leukemia Identify treatment strategies for each emergency Propose the role of the pharmacist in these emergencies Febrile Neutropenia Bone marrow suppression is a toxicity of many chemotherapy regimens Although all cell lines may be affected the reduction in leucocytes can be the most profound Patients absolute neutrophil count (ANC) is used to measure the degree of neutropenia Nadir ANC occurs 5-10 days after the last dose of chemotherapy Inpatient regimens, especially those used to treat hematologic malignancies, tend to produce greater depth and duration of neutropenia Chemotherapies with the Greatest Risk of Neutropenia Anthracyclines Taxanes Topoisomerase Platinums inhibitors Gemcitabine Vinorelbine Cyclophosphamide Ifosfamide Lewis M. et al. CA Cancer J Clin 2011;61: ANNUAL MEETING 3 Walji, N. et al. Postgrad Med J 2008;84: ANNUAL MEETING 4 Febrile Neutropenia Definition Fever Single temperature of 38.3 C Temperature of 38.0 C sustained over 1 hour Neutropenia ANC < 500 cells/mm 3 ANC expected to decrease to < 500 cells/mm 3 during the next 48 hours Patients categorized by high and low risk Clinically documented infection occurs 20-30% of the time Up to 70% mortality if initiation of antibiotics delayed Lack of fever does not necessarily rule out infection Neutropenic patients may not be able to mount an immune response and therefore may not have a localizing sign of infection or fever Lewis M. et al. CA Cancer J Clin 2011;61: Walji, N. et al. Postgrad Med J 2008;84: ANNUAL MEETING 5 Klastersky, J. et al. Ann of Onc. 2016;5: v111-v

2 Risk Factors MASCC Score High risk >7 days neutropenia ANC 100 cells/mm3 Hemodynamic instability Mucositis that interferes with swallowing or causes severe diarrhea New onset abdominal pain Pneumonia Neurologic changes Renal or hepatic impairment MASCC score of <21 Low risk 7 days neutropenia None or few active comorbidities MASCC score of 21 Characteristic Weight Burden of febrile neutropenia with no or mild symptoms 5 No hypotension (SBP > 90 mmhg) 5 No chronic obstructive pulmonary disease 4 Solid tumor or hematologic malignancy with no previous fungal 4 infection No dehydration requiring intravenous fluids 3 Burden of febrile neutropenia with moderate symptoms 3 Outpatient status 3 Age < 60 years ANNUAL MEETING ANNUAL MEETING 8 High Risk Treatment Antibiotics should be administered within 60 min of presentation Intravenous Antipseudomonal Monotherapy Cefepime 2g IV q8h Imipenem-cilastatin 500mg IV q6h Meropenem 1g IV q8h Piperacillin-tazobactam 4.5g IV q6h Advantages of B-lactam monotherapy over B-lactam plus aminoglycoside combinations include fewer adverse events and less morbidity Additional agent may be considered if antimicrobial resistance is suspected or in patients with complicated presentations such as pneumonia Special considerations Ensure all antibiotics are renally dosed appropriately Anaerobic coverage should be added for abdominal symptoms if not already covered by primary agent ANNUAL MEETING10 Gram Positive Organism Coverage Treatment Non-Responders Vancomycin and other gram positive antimicrobials are not recommended as part of the initial regimen but should be added in select patients If cultures remain negative for gram positive organisms, vancomycin should be discontinued within 2 3 days Indications for Addition of Antibiotics Active Against Gram Positive Organisms Hemodynamic instability or other evidence of severe sepsis Pneumonia documented radiographically Positive blood culture for gram positive bacteria Clinically suspected serious catheter related infection Skin and soft tissue infection at any site Colonization of Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococcus (VRE), or penicillin-resistant Streptococcus pneumoniae Severe mucositis, if patient received fluoroquinolone prophylaxis and patients receiving ceftazidime for empiric therapy Persistent fever Median time to fever defervescence following antibiotics is 2 days for solid tumor compared to 5 days with hematologic malignancies If patient is clinically stable no changes in antibiotic therapy is necessary but assessment for other infection sites should be performed Empiric antifungal coverage should be considered in patients with persistent fevers after 4-7 days of broad spectrum antibiotics and no identified source Non-responders with documented infection Examine and re-image for new or worsening sites of infection Culture/biopsy/drain sites of worsening infections Review antibiotic coverage including appropriate dosing Consider adding empiric antifungal coverage Broaden antimicrobial coverage if patient is hemodynamically unstable 2017 ANNUAL MEETING ANNUAL MEETING12 2

3 Fungal Coverage Duration of therapy Unexplained Fever > 4 days Infectious source identified Duration indicated for specific infection Continue until ANC 500 cells/mm 3 Receiving fluconazole prophylaxis Receiving antimold prophylaxis No infectious source identified Can discontinue antibiotics if afebrile for at least 48 hours and ANC is > 500 cells/mm 3 and showing a consistent increasing trend If patient received full course of antibiotics and all symptoms of infection have resolved, patients who remain neutropenic may stop empiric antibiotics and start antimicrobial prophylaxis therapy until bone marrow recovers Start antifungal based on results of CT scans of sinuses/chest Serial serum galactomannan test Empirical antifungal therapy with anti-mold coverage Echinocandin Voriconazole Amphotericin B Empirical antifungal therapy Consider to switch to a different class of mold active antifungal 2017 ANNUAL MEETING ANNUAL MEETING14 Colony Stimulating Factors Colony stimulating factors (CSF) such as granulocyte (G-CSF) and granulocytemacrophage (GM-CSF) are NOT recommended for routine use in patients with febrile neutropenia Infectious Diseases Society of America (IDSA) recommends against their use for all patients with fever and neutropenia American Society of Clinical Oncology guidelines state that their use can be considered in patients at high risk for infection associated complications or who have prognostic factors that are predictive of poor clinical outcome Special considerations if patient receiving filgrastim If subcutaneous absorption is altered, may administer filgrastim intravenously Dilute in D5W, administer over min If patient received peg-filgrastim, medication is eliminated by neutrophils Filgrastim (Neupogen TM ) Biosimilars A biosimilar is a biological product that it is highly similar to an FDA-approved biological product, known as a reference product, and has no clinically meaningful differences in terms of safety and effectiveness from the reference product Only minor differences in clinically inactive components Lower cost version Must have the same route of administration, dosage and strength as the original product Granix TM (tbo-filgrastim) Approved August 2012 Zarxio TM (filgrastim-sndz) Approved March 2015 Smith Tj, et al. J Clin Oncol.2015;33(28):3199 Lexicomp. Filgrastim. 5/1/2017 Adams K. Managed Care. April ANNUAL MEETING ANNUAL MEETING16 Guideline Recommendations Tumor Lysis Syndrome Guideline Recommendations National Comprehensive Cancer Network: Myeloid Growth Factors V All recommendations are category 2A Filgrastim (Neupogen TM ) Prophylactic use for febrile neutropenia (FN) Secondary prophylaxis for FN Management of patients with FN Filgrastim-sndz (Zarxio TM ) Prophylactic use for FN Secondary prophylaxis for FN Management of patients with FN Tbo-filgrastim (Granix TM ) Prophylactic use for FN Secondary prophylaxis for FN Tumor Lysis Syndrome (TLS) is a potentially life threatening medical emergency Metabolic derangements resulting from rapid cell death May occur spontaneously or in response to cytotoxic chemotherapy American Society of Clinical Oncology: Recommendations for the Use of WBC Growth Factors 2015 Filgrastim, tbo-filgrastim, filgrastim-sndz (and other biosimilars, as they become available) can be used for the prevention of treatment-related FN. The choice of agent depends on convenience, cost, and clinical situation. Smith TJ, et al. JCO.2015;33(28): NCCN V ANNUAL MEETING17 Mirrakhimov, A et al. World J Crit Care Med May 4;4(2):130-8 Photo: ANNUAL MEETING18 3

4 Pathogenesis Clinical Consequences When malignant cells lyse they release their contents into the bloodstream Cell Lysis Cells are rich in potassium, phosphorous and nucleic acids Accumulation of intracellular components mediates the complications associated with TLS Hyperkalemia, hyperuricemia, and hyperphosphatemia can have life threatening end organ effects on the myocardium, kidneys and central nervous system Hyperuricemia Hyperkalemia Hyperphosphatemia Hypocalcemia Renal insufficiency or failure Arrhythmias, Ventricular Tachycardia, Fibrillation, Cardiac Arrest Nausea/Vomiting, Diarrhea, Lethargy, Seizures, Renal Failure Cardiac Arrhythmias, Hypotension, Tetany, Muscle Cramps Lewis, M et al. CA Cancer J Clin. 2011;61: Mirrakhimov, A et al. World J Crit Care Med May 4;4(2): ANNUAL MEETING19 Mirrakhimov, A et al. World J Crit Care Med May 4;4(2): ANNUAL MEETING20 Pi, J et al. J Oncol Pharm Practice. 2016, Vol. 22(4); Diagnosis Cairo-Bishop Classification Element Value Change From Baseline Uric Acid 8 mg/dl (476 μmol/l) 25% increase Potassium 6 mg/l (6 mmol/l) 25% increase Phosphorus 1.45 mmol/l for 25% increase adults Calcium 1.75 mmol/l 25% decrease Requires the presence of laboratory abnormalities in addition to one or more of the following: Renal insufficiency (Cr 1.5 x upper limit of normal) Cardiac arrhythmias Seizures Sudden death Risk Factors Characteristic Tumor Type Tumor Burden/Extent of Disease Renal Function Baseline Uric Acid Risk Factor Burkitt s Lymphoma AML ALL Solid tumors with high proliferative rates and rapid response to therapy Bulky Disease (>10 cm) Elevated lactate dehydrogenase (>2X ULN) Elevated WBC (>25,000/mm 3 ) Preexisting renal failure Oliguria Serum/plasma uric acid > 7.5 mg/dl (450 μmol/l) Pi, J et al. J Oncol Pharm Practice. 2016, Vol. 22(4); Lewis, M et al. CA Cancer J Clin. 2011;61: ANNUAL MEETING ANNUAL MEETING22 Risk Factors Cancer Type High Risk Intermediate Risk Low Risk Management of TLS Non-Hodgkin s Lymphoma (NHL) Burkitt s lymphoma Diffuse large B-cell lymphoma Indolent NHL ALL WBC 100,000/mm 3 WBC 50, ,000/mm 3 WBC 50,000/mm 3 AML WBC 50,000/mm 3, monoblastic CLL WBC 10,000-50,000/mm 3 WBC 10,000/mm 3 WBC 10, ,000/mm 3 Treatment with Fludarabine WBC 10,000/mm 3 Low Risk Patient: Clinical judgment + monitoring Intermediate Risk Patient: Hydration + Allopurinol; If hyperuricemia develops start rasburicase High Risk Patient: Hydration + Rasburicase Lewis, M et al. CA Cancer J Clin. 2011;61: ANNUAL MEETING23 Mirrakhimov, A et al. World J Crit Care Med May 4;4(2): ANNUAL MEETING24 4

5 Management of TLS Alkalization of Urine Hydration is the mainstay of prophylaxis and treatment of TLS Promotes excretion of uric acid and phosphate by improving Intravascular volume Renal blood flow Glomerular filtration Twice the rate of usual maintenance fluids Diuretics may be necessary to maintain adequate urine output Goal urine output: 80 to 100 ml/m 2 /hour in adults Use of sodium bicarbonate to alkalinize the urine Historically recommended but use is controversial In an acidic urinary filtrate environment, uric acid will precipitate in the renal tubule Alkalization increases uric acid solubility by increasing the percentage of ionized uric acid in urine Limitations: Metabolic alkalosis and calcium phosphate precipitation Due to lack of clear benefit, the use of sodium bicarbonate for the prevention/treatment of TLS is not recommended Correction of electrolytes Davidson, M et al. Am J Med Apr 15;116(8): ANNUAL MEETING ANNUAL MEETING 26 Allopurinol Allopurinol Dosing Administer 1 to 2 days prior to initiation of chemotherapy, continue for 3 to 7 days after chemotherapy Limitations: Ineffective in reducing preexisting levels of uric acid Used prophylactically in patients with intermediate risk factors for TLS in conjunction with hydration Dosage Form Dose Oral (100 mg and 300 mg tablets) 10mg/kg q8h in divided doses (max 800 mg/day) Or mg/m 2 q8h (max 300 mg/m 2 /day) Intravenous (500 mg vial) 200 to 400 mg/m 2 daily (max 600 mg/day) in 1 to 3 divided doses 2017 ANNUAL MEETING ANNUAL MEETING28 Rasburicase Rasburicase Dosing Intermediate or high risk for developing TLS in conjunction with hydration Limitations: Contraindicated in G6PD deficiency and price TLS Profile Baseline Uric Acid *Vial size: 1.5mg ampule and 7.5mg vial Dose High Risk >7.5 mg/dl 0.2 mg/kg/dose 6mg/dose Intermediate Risk <7.5 mg/dl 0.15 mg/kg/dose 3mg/dose Duration Based on plasma uric acid levels Based on plasma uric acid levels 2017 ANNUAL MEETING ANNUAL MEETING30 5

6 Rasburicase Serum uric acid monitoring Levels may be collected 4 hours after rasburicase administration, then every 6 to 8 hours until TLS resolution Black Box Warning: Interference with uric acid measurements Enzymatically degrades uric acid in blood samples left at room temperature Collect blood samples in pre chilled tubes containing heparin and immediately immerse and maintain sample in an ice water bath Assay samples within 4 hours of collection Rasburicase Dosing Strategies 3mg versus 6mg dosing Examine the comparative effectiveness of a single 3 mg versus 6 mg dose Design: Retrospective cohort study N= 108 adults with hematological malignancies and baseline uric acid 12 mg/dl Outcome: Percentage of patients that achieved a uric acid 8 mg/dl 24 hours after a single dose of rasburicase 2017 ANNUAL MEETING ANNUAL MEETING32 Kraus, SK et al. Blood :4511 Rasburicase Dosing Strategies Rasburicase Dosing Strategies 3mg versus 6mg dosing 3mg versus 6mg dosing Mean baseline uric acid was 9.3 mg/dl and 9.8 mg/dl in the 3 mg arm and 6 mg arm, respectively (p= 0.19) At 24 hours there was no difference in the percentage of patients who achieved a uric acid 8 mg/dl (p= 0.36) o3 mg arm: 92% o6 mg arm: 98% 6 mg arm had a greater percent reduction in uric acid from baseline compared to the 3 mg arm at both 24 hours (p <.01) and 48 hours (p= 0.02) after rasburicase administration A single 3 mg dose of rasburicase was as effective as 6 mg in normalizing uric acid within 24 hours in patients presenting with a uric acid 12 mg/dl Six (11.5%) patients in the 3 mg arm and one (1.8%) patient in the 6 mg arm required a second dose of rasburicase to achieve a uric acid 8 mg/dl (p= 0.1) 2017 ANNUAL MEETING ANNUAL MEETING34 Kraus, SK et al. Blood :4511 Kraus, SK et al. Blood :4511 Chemotherapy in ICU Hypercalcemia of Malignancy Patients with TLS may require continuation or new start of chemotherapy in the ICU Special considerations Nurses certified to administer chemotherapy Premedication, including hydration Adverse reactions of chemotherapy Chemotherapy interactions with other medications Renal dosing of chemotherapy agents including IHD and CVVHD dosing Metabolic emergency that occurs in 20-30% of cancer patients Breast, lung and renal cell carcinomas; multiple myeloma; and adult T-cell leukemia/lymphoma are the most common malignancies Hypercalcemia often indicates poor prognosis Pi, J et al. J Oncol Pharm Practice Vol 22(4): ANNUAL MEETING35 Lewis, M et al. CA Cancer J Clin.2011;61: ANNUAL MEETING36 Photo: 6

7 Pathogenesis Presentation Several mechanisms can explain elevated calcium Systemic release of parathyroid hormone related peptide (PTHrP) by the tumor Local paracrine stimulation of osteoclasts by metastases to the bone Systemic secretion of Vitamin D analogues by the tumor 80% caused by PTHrP released by the tumor into circulation PTHrP can mimic the actions of the parathyroid hormone (PTH) on the bone and kidney Increase bone resorption and renal retention of calcium Classification Ca level Symptoms Mild mg/dl Usually asymptomatic Moderate mg/dl +/- symptoms Severe > 14 mg/dl Symptomatic Symptoms Skeletal pain Dehydration Gastrointestinal symptoms Altered mental status Coma Nephrolithiasis Polyuria Cardiac arrhythmia Vascular calcification Lewis, M et al. CA Cancer J Clin.2011;61: ANNUAL MEETING 37 Pi, J et al. J Oncol Pharm Practice Vol 22(4): ANNUAL MEETING38 Lewis, M et al. CA Cancer J Clin.2011;61: Treatment Treatment Continued Medication Mode of Action Dose Onset Comments Medication Mode of Action Dose Onset Comments Hydration (0.9% NS) Furosemide Calcitonin Enhances GFR and renal excretion of calcium Inhibits calcium resorption in the renal tube Inhibits bone resorption 500-1,000 ml bolus followed by ml/hr Rapid Caution with HF patients mg IV daily min Avoid until euvolemic 4 8 IU/kg SC or IV every 8 12 hr min Max response within hr, tachyphylaxis Pamidronate Zoledronic acid Denosumab Glucocorticoids Inhibits osteoclast activity; decreases bone resorption Inhibits osteoclast activity; decreases bone resorption Inhibits RANKL to decrease osteoclast activity Inhibits vitamin D conversion to calcitriol mg IV over 2-6 hr in ml of NS or D5W hr Use with caution in renal impairment, allow 7 days before re-dosing 4 mg IV over min hr Use with caution in renal impairment, allow 7 days before re-dosing 120 mg SC every 4 weeks; administer additional 120 mg on days 8 and 15 during the first month Prednisone po 60 mg daily, hydrocortisone 100 mg IV q6h hr Used in refractory hypercalcemia at least 7 days after a bisphosphonates 1 2 hr Chronic use should be avoided Pi, J et al. J Oncol Pharm Practice Vol 22(4): Lewis, M et al. CA Cancer J Clin.2011;61: Pi, J et al. J Oncol Pharm Practice Vol 22(4): ANNUAL MEETING ANNUAL MEETING Lewis, M et al. CA Cancer J Clin.2011;61: Bisphosphonates Pamidronate vs Zoledronic Acid First line medication for hypercalcemia There is evidence that zoledronic acid may be superior to pamidronate in the treatment of moderate to severe hypercalcemia Zoledronic acid 4mg or 8mg compared to pamidronate 90mg for moderate to severe hypercalcemia Randomized, double blind, controlled trial N= 287 Both doses of zoledronic acid were superior to pamidronate Complete response rates by day 10 were 88.4% (P 5.002), 86.7% (P 5.015), and 69.7% for zoledronic acid 4 mg and 8 mg and pamidronate 90 mg, respectively Conclusion: zoledronic acid is superior to pamidronate; 4mg is the dose recommended for initial treatment and 8mg for relapsed or refractory hypercalcemia Clinical significance of this difference is controversial Major,P et al. J Clin Oncol, Vol 19, No 2 (January 15), 2001: Pi, J et al. J Oncol Pharm Practice Vol 22(4): ANNUAL MEETING41 Major,P et al. J Clin Oncol,Vol 19, No 2 (January 15),2001: ANNUAL MEETING42 7

8 Acute Promyelocytic Leukemia (APL) APL is an aggressive subtype of acute myeloid leukemia (AML) Rare disease, accounting for 5-10% of all AMLs in adults APL is a medical emergency High rate of early mortality if not treated Life threatening hemorrhages can occur, most severe in brain and lungs Patients can present with thrombosis, very rare Can be diagnosed at any age but typically younger than other AML subsets May present after treatment of a primary cancer Schwartz LM, et al. N Engl J Med. 361; : ANNUAL MEETING Cicconi, L. et al. Ann of Onc : ANNUAL MEETING44 NCCN Version 2:MS11-MS23 Presentation Initial Management Signs and symptoms Petechiae Bruising Severe bleeding, including intracranial or pulmonary Thrombosis Consumptive coagulopathy is present at diagnosis in about 80% of patients Hypofibrinogenemia Thrombocytopenia Increased PT, PTT, D-Dimer Cicconi, L. et al. Ann of Onc : ANNUAL MEETING ANNUAL MEETING46 Cicconi, L. et al. Ann of Onc : First Line Therapy Induction Therapy Given the risk of hemorrhagic events, treatment should be started immediately All-trans retinoic acid (ATRA) ATRA produces differentiation in APL blasts that can reverse coagulopathy As a single agent, ATRA was reported to induced complete response rates of 85% However, when using ATRA alone, remission rates are short lived with a median duration of 3.5 months Using ATRA based induction therapy with anthracyclines are associated with clinical response rates exceeding 90% Arsenic trioxide (ATO) Potent promoter of apoptosis in APL cells Has been studied as a single agent or in combination with ATRA for low/intermediate risk APL Clinical response rates exceeded 90% with ATO alone or in combination with ATRA Low or Intermediate risk patients (WBC counts 10,000/mcL) ATRA + ATO ATRA + idarubicin alone ATRA + daunorubicin + cytarabine High risk patients (WBC counts > 10,000/mcL) ATRA + cytarabine+ daunorubicin ATRA + idarubicin ATRA + ATO + idarubicin Cicconi, L. et al. Ann of Onc : NCCN Version 2:MS11-MS ANNUAL MEETING ANNUAL MEETING48 NCCN Version 2:MS11-MS23 8

9 Treatment ATRA Dosing: 45mg/m 2 /day po divided into two doses Available in 10mg capsules Cannot crush, chew or dissolve capsule Adverse events: Headache Fever Dry skin and mucous membranes ATO Dosing: 0.5mg/kg/day IV Administered over 1 2 hours The rate may be extended to 4 hours if patient develops a vasomotor reaction Adverse events: Tachycardia Eyesight changes Eyesight changes Infections pain Low potassium and magnesium Rash Treatment Adverse Events NCCN Version 2:MS11-MS23 Lexicomp. 5/1/ ANNUAL MEETING49 Cicconi, L. et al. Ann of Onc : ANNUAL MEETING50 ATRA Administration via Feeding tube Per package insert ATRA is not to be crushed or dissolved Critical patients who require mechanical ventilation cannot swallow capsules Case reports have successfully prepared ATRA to be given via feeding tube Case Report 1 Case Report 2 Case Report 3 10 ml distilled water heated to Daily amount of ATRA is placed 45 C and ATRA added. 5mL of in a sterile 50 ml tube. After mineral oil added to work as addition of about 20 ml of sterile lipophilic carrier. Drawn in a 20mL water the tube is heated in a syringe and shaken until water bath to a temperature of dissolved. Liquid given via 37 C until the capsules melt and feeding tube. the suspension is completely liquid. The resulting oily fluid is then administered via nasogastric tube. ATRA capsules were opened, the free powder aspirated into a glass syringe, and the remaining capsule contents suspended in soy bean oil and aspirated into the same syringe FSHP 2017 ANNUAL MEETING Special Considerations for the Oncology Patient in the ICU Ashley Valverde, PharmD, BCPS Rev Bras Hematol Hemoto.2017;39(1):86-88 Bargetzi, MJ, et al. Schweiz Med Wochenschr. 1996;126(45): Preet, M, et al. Blood. 2011; 118: ANNUAL MEETING