Chemotherapy: Nuts and Bolts

1. Chemotherapy: Nuts and Bolts Jennifer M. Pope, MD

2. Chemotherapy dosing • In general, done by body surface area • √Weight in kg x height in cm 3600 • Intrathecal chemotherapy • Dosed by age • Be very careful with infants, many drugs dosed by kg instead of BSA if patients is < 10kg • In general, don’t bother with decimals greater than tenths • i.e. 2.1 mg is fine, 2.14mg should be rounded to 2.1, 2.16mg rounded to 2.2mg

3. General principles • Most chemotherapeutic agents have significant toxicities, even those that are “targeted” • i.e. imatinib (Gleevec) can cause myelosuppression, transaminitis • Some toxicities are common (alopecia, myelosuppression, nausea/vomiting, mucositis), they occur with greater severity or frequency with certain agents • Other toxicities are rare, but can be severe, and are specific to certain agents • Knowledge of idiosyncracies of specific agents is critical to safe management of patients

4. Nausea/Vomiting • Experienced by 70% to 80% of cancer patients • Types of emesis: • Acute: begins within two hours of chemotherapy without prophylaxis • Delayed: begins 24 hours after chemotherapy complete • Anticipatory: conditioned response to previous cycles of highly emetic chemotherapy

5. Pathophysiology • Neuroanatomy • Five neurotransmitter receptor sites are of primary importance in the vomiting reflex: • M1 – muscarinic • D2 – dopamine • H1 – histamine • 5-HT3 – serotonin • NK1 – substance P

6. Nausea/Vomiting • Incidence and severity related to: • Emetic risk of the chemotherapeutic agent • Dose • Schedule • Route of administration • Patient variability

7. High (>90%) Moderate (30% to 90%) Low (10% to 30%) minimal (<10%) Emetic risk

8. Anti-emetics • Serotonin [5-HT3] antagonists (ondansetron and granisetron) • inhibit chemoreceptor trigger zone of the area postrema • acute nausea • Most common side effect is headache • EKG changes may occur • Corticosteroids (dexamethasone) • Mechanism of action unknown • Best in combination with 5-HT3 antagonists • Do not give to leukemia/lymphoma patients • Side effects: mood disturbance, hyperglycemia, insomnia • Benzodiazepines (lorezepam) • Weak antiemetics when low doses are used • Anticipatory nausea

9. Anti-emetics (cont) • Antihistamines (diphenhydramine) • May be used alone or in combination • Sedation is the major side effect • Dopamine antagonists (phenergen) • use with diphenhydramine to prevent dystonia • do not give to kids < 2 years of age • Neurokinin-1 receptors (aprepitant) • acute and delayed • CYP3A4 inhibitor so watch out for drug interactions • Adolescents/young adults • Scopolamine • Cannabinoids

10. ASCO Guidelines • High (90%) emetic risk. 5-HT3 serotonin receptor antagonist, dexamethasone, and aprepitant is recommended before chemotherapy (includes anthracycline/cyclophosphamide combination). • Moderate (30% to 90%) emetic risk. Two-drug combination of a 5-HT3 receptor serotonin antagonist and dexamethasone. • Low (10% to 30%) emetic risk. Dexamethasone premedication (adult recs, we tend to use 5-HT3 receptor serotonin antagonist) Kris MG. J Clin Oncol 24:2932-2947, 2006

11. Hydration • Certain agents require hyperhydration to facilitate excretion and/or protect from associated toxicity • Ifosfamide/cyclophosphamide, methotrexate (high-dose, > 1g/m2), cisplatin/carboplatin • Patients receiving these agents will have strict I/Os recorded, and urine dipped for specific gravity, blood, and pH  this is a source of many questions overnight! • In some cases, in order to maintain adequate urine output, you may need to give NS bolus or lasix  check the protocol and ask the attending if you are not sure!

12. Allergic Reaction • Allergic reactions range from itching to anaphylaxis • Emergency meds include • Epinephrine: 0.01 mg/kg (0.01 mL/kg/dose of 1:1000 solution) not to exceed 0.5 mg SUBCUTANEOUS • Diphenhydramine: 1 mg/kg Intravenous • Either • Hydrocortisone: 1 mg/kg IV • Methylprednisolone: 1mg/kg IV

13. Allergic Reaction • Agents requiring bedside emergency medications: • Asparaginase (all forms) • Etoposide • ATG (anti-thymocyte globulin • Bleomycin • Carboplatin • Doxetaxel • Doxorubicin (liposomal form only) • Any of the monoclonal anitbodies (rituximab, infliximab, gemtuzamab, Campath, etc)

14. Chemotherapy Extravasation • Irritant vs. vesicant • Irritant causes an inflammatory reaction without tissue sloughing or necrosis. • Extravasation of a vesicant drug has potential to cause tissue necrosis • Dactinomycin, Taxanes, Anthracyclines, Mechlorethamine, Oxaliplatin, Vinca alkaloids • Key is prevention – free-flowing IV, preferably central line with confirmed position • Treatment: • Stop the infusion immediately. Do not flush the line, and avoid applying pressure to the extravasated site. • Elevate the affected extremity. • Attempt to aspirate fluid from the extravasated area • Apply antidote, if available • Topical application of ice or cold packs is recommended for extravasation of all vesicant or irritant drugs except the vinca alkaloids (vincristine, vinblastine, vinorelbine) and epipodophyllotoxins such as etoposide. Intermittent cooling is thought to cause vasoconstriction, thereby diminishing the spread of the drug and the extent of the local injury. Cold compresses also reduce local inflammation and pain. • Application of ice is contraindicated for extravasations of vinca alkaloids or epipodophyllotoxins, as cold worsens the ulceration caused by these drugs, at least in animal models. Instead, the application of heat is generally recommended for these agents.

16. Cytarabine (Ara-C) • Synthetic analogue of the naturally occurring nucleoside cytidine • Intracellularly converted to AraCTP which is a potent inhibitor of DNA replication by competitive inhibition of DNA polymerase; also incorporates into the DNA strand acting as a relative chain terminator • May be intrathecal, low-dose or high-dose • Unique side effects • Conjunctivitis: high-dose regimens include steroid eye drop prophylaxis • Neurotoxicity: headache, malaise, confusion, seizures, fever, irritability, cerebral and cerebellar dysfunction (somnolence, personality changes, coma, ataxia) • Hand-foot syndrome: palmar plantar erythrodesia • Risk of life-threatening infection: prolonged and profound neutropenia, high rate of viridans streptococcal sepsis and translocation of other oral mucosal organisms  empiric vancomycin for any fever • Ara-C syndrome: fever, myalgia, bone pain, rash, conjunctivitis, malaise occurring 6-12 hours after administration (if severe, may require treatment with dexamethasone) NOTE: if fever, assume infection until proven otherwise

17. Hemorrhagic Cystitis • Oxazaphosphorine alkylating agents (Cyclophosphamide/ifosfamide) • Etiology: urinary excretion of hepatic metabolite acrolein • Diffuse bladder mucosal inflammation with hemorrhage • Bleeding can range from minimal (5 to 50 RBC per high powered field), to massive, requiring transfusion • Incidence increases with higher individual doses, larger cumulative doses, and ifosfamide > cyclophosphamide

18. Hemorrhagic cystitis 2 • PREVENTION • hyperhydration (125-200mL/m2/hr, Urine Specific Gravity < 1.010 prior to start of chemotherapy, maintain urine output >2-3mL/kg/hour) • If urine output dropping off, give NS bolus or lasix • Remember that cyclophosphamide can rarely cause SIADH, so if the urine output dropping in spite of fluids, get serum Na, Cr, Osm • MESNA: Within minutes of intravenous administration, mesna is oxidized to a stable inactive disulfide in the serum but is reactivated in the kidney. In the urine, it binds to acrolein, creating an inert thioether that is excreted • The serum half-life of mesna is 90 minutes, while cyclophosphamide and ifosfamide have half-lives of six and seven hours, respectively. Mesna must be present in the bladder at the time of chemotherapy administration in order to be effective. Usually dosed at 60% of cyclophosphamide/ifosfamide dosing). • MESNA fun fact: makes urine positive for ketones!

19. What do you do if there is hematuria? • Noted on urine dip only, send formal U/A (consider urine culture, BK virus). • If persistent microscopic hematuria (>2 abnormal urinalyses during a cycle of therapy) increase hydration to 3500-4000 ml/m2/day and daily MESNA dose to 100% of the cyclophosphamide or ifosfamide dose. • Gross hematuria: STOP the chemo! Change fluids and MESNA as above. Call urology as may need continuous bladder irrigation

20. Ifosfamide: nephrotoxicity • In addition to hemorrhagic cystitis, ifosfamide is directly nephrotoxic due to direct tubular injury (cyclophosphamide is not) • The metabolite chloracetaldehyde is toxic to tubular cells, rather than the parent drug or acrolein • At equivalent doses, the rate of chloracetaldehyde generation with ifosfamide is 40 times greater than with cyclophosphamide • Another possible mechanism of toxicity may be energy depletion via mitochondrial damage

21. Ifosfamide (continued) • Clinical manifestations (Fanconi renal syndrome – proximal tubule damage) • Hypophosphatemia glucosuria, aminoaciduria, tubular proteinuria (ie, low molecular weight proteins but not albumin) • Polyuria due to nephrogenic diabetes insipidus  rare • Renal potassium wasting, which may cause severe hypokalemia • Metabolic acidosis with a normal anion gap (hyperchloremic acidosis) due to type 1 (distal) or type 2 (proximal) renal tubular acidosis. • May be transient infusions, and become persistent as cumulative dose increases • Can lead to mild reduction (20-30% below baseline) in GFR • Risk factors: age < 5 years, concurrent cisplatin therapy, and cumulative ifosfamide dose above 60 g/m2 with severe nephrotoxicity primarily occurring at a total dose of 120 g/m2 or more

22. Ifosfamide: neurotoxicity • 2-5% of children, 10-15% of adults • increased with a prior history of ifosfamide-related encephalopathy, renal dysfunction, low serum albumin, or prior cisplatin treatment, may be increased with use of aprepitant • Complex mechanism • chloroethylamine, a metabolite of ifosfamide conjugates with cysteine forming thialysine, which is metabolized to thialysine ketimine, which inhibits electron-binding flavoproteins and, consequently, mitochondrial respiration. The consequence is NADH accumulation and prevention of the inactivation of chloracetaldehyde, a neurotoxic metabolite of ifosfamide • Translation: looks like alcohol intoxication (where the neurotoxic substance is acetaldehyde)

23. Neurotoxicity (continued) • Symptoms include somnolence, lethargy, irritability, excitement, disorientation, confusion, weakness, asterixis, hallucinations, seizures. • Normally rare and transient. Rarely severe and progressive. • What to do? • STOP the infusion. Evaluate for other causes of altered mental status • Methylene blue: acts as an electron accepting agent, thereby correcting derangement in mitochondrial flavoproteins. It prevents encephalopathy by a different mechanism when used prophylactically, namely oxidation of excessive NADH formed during ifosfamide • Downsides: modest efficacy, side effects include nausea, abdominal pain, dizziness, headache, profuse sweating, confusion, methemoglobinemia • Thiamine: not sure how it works, case reports, non-toxic.

24. Methotrexate • Used in many doses and formulations in ALL, lymphoma, osteosarcoma • Toxicities include myelosuppression, mucositis, renal toxicity, hepatic toxicity, neurotoxicity • acute elevation in the serum transaminases from 2-20x normal levels, even in patients who receive leucovorin rescue. Acute transaminitis occurs in as many as 60 to 80 percent of patients and typically resolves spontaneously within one to two weeks. • Myelosuppression usually mild with leucovorin rescue • IT MTX is eliminated from the cerebrospinal fluid by slow passive diffusion into the systemic circulation. Because of this, some recommend a short course of leucovorin rescue for patients with renal dysfunction AND patients with Down syndrome

25. Methotrexate: mechanism • Dihydrofolate reductase (DHFR) converts dihydrofolate to tetrahydrofolate, thus continuously replenishing the cell's supply of reduced folates. • At high doses, MTX is polyglutamated and remains intracellular • More active • More toxic

26. Methotrexate excretion • 90% renal excretion (MUST dose adjust in renal impairment) • Rapidly excreted in urine, insoluble at pH< 7.0, if accumulates can precipitate in tubules and cause renal failure • Hydration and alkalinization to urine pH 7-8, specific gravity < 1.010 is IMPERATIVE. • Do not start MTX until urine parameters are met! Can give NS and bicarbonate boluses. Monitor urine parameters until MTX is excreted below 0.1uM. • Protocols specify acceptable levels at different time points (i.e. 24, 42, 48 hour levels). If elevated, increase hydration to 200mL/m2/hr and leucovorin rescue per protocol. • If level is unacceptably high, consider Glucarpidase (carboxypeptidase G2) to rapidly lower serum MTX levels

27. Methotrexate (continued) • Many drugs inhibit renal excretion of MTX and may increase treatment-related toxicity. STOP these in advance of HD-MTX infusion • NSAIDs, phenytoin, ciprofloxacin, penicillin-type drugs, probenecid, amiodarone, and proton pump inhibitors • Bactrim (trimethoprim/sulfamethoxazole) increases toxicity and may interfere with efficacy • Sulfa drugs inhibit MTX renal excretion, while trimethoprim (also an antifolate) compete with MTX for binding sites on DHFR • Third-space fluid collections (eg, ascites, pleural effusions) can accumulate high levels of the drug that slowly leak back into the circulation long after the initial dose.

28. Leucovorin rescue • MTX has little selectivity for tumor cells, and its effectiveness is limited by toxicity to normal tissue, particularly the gastrointestinal (GI) epithelium and bone marrow. • Rescue normal cells from toxicity by providing reduced folates (leucovorin) 24-42 hours after administration of MTX • Dosing: usually 15mg/m2 q6hr starting at hour 24-42 depending on protocol, increase to q3h or higher doses depending on levels. Continue until MTX level < 0.1uM • Why does it work? • folate transport is deficient in malignant cells? • leucovorin cannot be transported into the malignant cell, but it can enter normal cells and compete with MTX for binding sites on DHFR because they retain a normal folate carrier protein • cellular differences in polyglutamation? • Intracellularly, leucovorin is able to compete with free but not polyglutamated MTX for binding to DHFR In contrast to tumor cells, comparatively little PGMTX synthesis occurs in normal gut epithelium and bone marrow precursors under similar conditions. It is hypothesized that because of the lower levels of intracellular PGMTX, leucovorin can more effectively curtail DHFR inhibition in normal as compared to malignant cells.

29. MTX neurotoxicity • Leukoencephalopathy • White matter changes on MRI • Variable incidence, common in patients on therapy, but in many cases is transient and resolves after completion of therapy • Clinical presentations • Most asymptomatic • Acute encephalopathy with transient focal neurologic deficits (~3-5%): stroke-like (hemiparesis, aphasia), seizures, tranverse myelitis • Evaluate for stroke (especially if recent asparaginase), infection, hypertension • Treatment: often resolves with supportive care, other options in case series include aminophylline (antagonizes effect of increased adenosine), dextromethorphan (NMDA antagonist) • Chronic encephalopathy • Demyelination, calcifications • Exacerbated by cranial radiation • Neurocognitive difficulties

30. Platinum compounds • Cisplatin (osteosarcoma, germ cell tumors, CNS) • highly emetogenic • Nephrotoxicity with selective proximal tubule injury – may be abrupt, or insidious with cumulative dosing • Often heralded by hypomagnesemia (which can exacerbate cisplatin toxicity), can have Fanconi renal syndrome and falling GFR • PREVENTION with forced diuresis, replete magnesium • High rate of fluid administration • Mannitol diuresis • Other toxicities: axonal neuropathy, dose-dependent high-frequency sensorineural hearing loss

31. Carboplatin • Significantly less nephrotoxic than cisplatin • Can see magnesium and salt-wasting • Renal clearance is critical, dosing by AUC (area under curve) and GFR rather than body surface area  Calvert formula • Infusion reaction/anaphylaxis: 12-30%, increases with repeated exposure

32. Vincristine • Vinca alkaloids, mechanism = microtubule disruption • Dose-limiting toxicity is axonal neuropathy involving both sensory and motor fibers, with small sensory fibers most affected • Virtually all patients have some degree of neuropathy. • Earliest symptoms = paresthesias in the fingertips and feet, +/- muscle cramps. • Loss of DTRs is universal. May have bilateral foot drop, wrist drop • Occasional severe weakness should cause you to look for underlying disorder (Charcot-Marie-Tooth) • There is no treatment • PT/OT critical, Gabapentin to manage pain symptoms • Dose reduction ONLY if severe • Natural history is gradual improvement after cessation of therapy over months or longer.

33. Vincristine (cont) • Autonomic neuropathies : Colicky abdominal pain and constipation common. All patients should have prophylactic stool softeners or laxative. Occasional paralytic ileus. To give VCR, must be stooling and have bowel sounds! • Focal neuropathies: most common oculomotor nerve, facial nerve (jaw pain), recurrent laryngeal nerve (vocal cord paralysis) • SIADH, resulting in hyponatremia, confusion, and seizures • Other rare CNS complications that are unrelated to SIADH include seizures, encephalopathy, transient cortical blindness, ataxia, athetosis (slow, writhing movements of the limbs), and parkinsonism • VCR is fatal if administered intrathecally

34. Asparaginase • Breaks down extracellular asparagine into aspartic acid and ammonia • Unlike normal cells, lymphoblasts lack the enzyme to synthesize asparagine and therefore rely on an exogenous source of this amino acid to maintain cellular protein synthesis. • Pegylated E.coli-derived formulation has prolonged half-life (six days), least immunogenic • Hyperlipidemia (TG), hyperglycemia (especially with concurrent steroids, manage with insulin, do not change dose!), hyperammonemia • Allergic reaction • 5-10% of patients • Indication to switch to Erwinase (Erwinia-derived, non-pegylated) if systemic anaphylaxis (33% recurrence)

35. Asparaginase (cont) • Pancreatitis • 2-7% of patients, increased in adolescents • Typically occurs within four weeks of first dose of asparaginase • Symptomatic pancreatitis associated with high rate of recurrence with retreatment, but strongly consider retreatment as asparaginase is a key component of ALL therapy. • Chronic complications uncommon but can develop pseudocysts • Coagulopathy due to decreased protein synthesis of clotting factors with reductions in plasminogen, fibrinogen, antithrombin, protein C/S, and factors IX and X with prolonged aPTT • Usually results in thrombosis (catheter-related 5% symptomatic, venous sinus thrombosis 2.9%, DVT 5-10%) • More common in induction than later in therapy • If thrombosis, perform inherited thrombophilia evaluation (i.e. Factor V Leiden etc), treat with lovenox, replete AT3 • Hepatic toxicity • 20% transaminase elevations, 3% hyperbilirubinemia, mostly mild and transient

36. Etoposide • Anaphylaxis • Hypotension with rapid IV infusion • Must run over 30-60min • Must be diluted minimum of 0.4mg/mL • If diastolic or systolic blood pressure (BP) falls 20 mm Hg during infusion, reduce infusion rate by 50%. Start a simultaneous infusion of NS 10 ml/kg if BP fails to recover or falls further. • Stop infusion if BP does not recover, continue NS. If the patient has had any episode of hypotension, prehydrate with 0.9% NaCl at 10 mL/kg/hr for 2 hours prior to any subsequent infusion.

37. Doxorubicin • Anthracycline antibiotic • Intercalates between DNA double helix and inhibits topoisomerase II • Red going in, red coming out • Significant toxicities: • Cardiovascular – acute and delayed • Nausea/vomiting • Mucositis • Radiation recall

38. Other drugs for another day… • ATRA – pseudotumor cerebri • Bleomycin – pulmonary fibrosis • Mercaptopurine/thioguanine • Myelosuppression • TPMT deficiency • Veno-occlusive disease