2. Oncologic Emergencies Prof. Dr. Khaled Abouelkhair, PhD Medical Oncology SCE, Royal College, UK Ass. Professor of Clinical Oncology Mansoura University, Egypt

3. Hypercalcemia Hyperuricaemia / TLS Cord Compression

4. Drugs…errors and prevention

5. Health care is committed to patient’s safety… so why Too many medical errors do occur everyday

6. Imipenem 1000 mg I.V q 6h in a patient with renal impairment. How many errors in this prescription? What is the maximum dose of Imipenem in such situations with renal impairment? When this error was discovered I realized why western countries always emphasis that we should always have a good system to follow doing our job rather than depending on individual expertise.

7. On Thursday 4th January 2001, A Mr WJ, a day case patient at the Queen’s Medical Centre Nottingham U.K, was prepared for an IT administration of chemotherapy as part of his medical maintenance program following successful treatment of leukemia. After carrying out a lumbar puncture and administering the correct cytotoxic therapy (Cytosine) under the supervision of the Specialist, Dr Morton, a Senior House Officer, was given a second drug administer to Mr WJ, which he subsequently did. However, the second drug, Vincristine, should never be administered by the intrathecal route because it is almost always fatal. This is just a single example for too many daily errors that could happen.

8. Deadly Story of Medication Errors  Pilot study in 2 London hospitals:  What is clear is that we need to know more about errors and do more about them Sir George, BMJ March 2002 Adverse events in >1 in 10 pts 1/3 of these are serious

9. Trajectory Most errors result from multiple contributing failures (holes). The trajectory path shows that several layers of protection had been lost increasing the likelihood of harm to occur. No one is immune. Lab. Oncologist Pharmacist Administration Fatal Error

10. How could that apply to Oncology? Simply we can kill our patients

11. ONCOLOGIST ERRORS  Lack of experience..  Work load  Improper protocol..R-CHOP for H.D  Serious combinations…NSAIDS + HDMTX  Unawareness of co-morbidities.. H.F, CRF  Unawareness of drug side effects..Allergies…..examples…premedication  Dose modifications  Premedications and post chemotherapy treatment A good pharmacist always review the drugs, doses, dose reductions, number of cycles and appropriate protocols.

12. PHARMACIST ERRORS  Who can tell me…..? ALWAYS WATCH THE OTHERS’ MISTAKES  If the pharmacist layer failed to correct other’s mistakes……this is a fatal error.  Always remember pharmacists are our safe guards coming in the middle between prescription and administration

13. What you should check for? The Simple Five Rules R’s  Right Patient  Right Drug  Right Dose  Right Route  Right Time

14. Take Home Messages  We are dealing with serious drugs for serious disease affecting miserable patients… Please don't add to their misery.  Remember your safety layer…. Close any holes that could be there  As being oncologists, we always depend up on you to catch on and correct our mistakes.. Please do not fail us.

15. A patient admitted in the medical floor, known case of lung cancer metastatic to bone, the nurse reporting that the patient is Lethargic, stupor, as well as Fatigue, Dehydration and constipation. ECG was requested which revealed Cardiac bradycardia, and short QT interval What would it be? Metabolic or Neurologic?

16. The calcium ion plays a critical role in normal cellular function and signaling (neuromuscular signaling, cardiac contractility, hormone secretion, and blood coagulation).

17. Feedback mechanisms maintaining extracellular calcium concentrations within a narrow, physiologic range. Normal Ca level (8.9 – 10.1 mg/dl). Corrected Ca mg/dl = (4- albumin in g/dl) x 0.8 + serum Ca. Commonest Cancer NSCLC, SCLC, Breast, M.M, RCC, and NHL (T-cell). Causes of Hypercalcemia: – Direct bone destruction – Immobilization – Parathormone like hormones – Medications e.g. Thiazides, Antiestrogens, Vit A – Excessive calcium intake, milk alkali syndrome

18. Management First be sure it is true hypercalcemia? The second most important laboratory test in the diagnostic evaluation is a PTH level. Serum creatinine should be measured to assess renal function. Mild Hypercalcemia: asymptomatic patients with minimally elevated calcium levels (< 12.0 mg/dL) …Encouragement of oral hydration, mobilization, and elimination of drugs that contribute to hypercalcemia are essential. 2-3 L of intravenous fluid may be required over the first 24 h

19. Moderate Hypercalcemia: 12 -14 mg/dl symptomatic directed therapy. Severe Hypercalcemia: ≥ 14 mg/dl. Emergency – Hydration 3-6 L/24h. – Loop diuretics. Furosemide, 20 to 40 mg IV, may be initiated after volume expansion is achieved, with subsequent doses given when urine output is < 150 to 200 mL/h. Thiazides are contraindicated. – Bisphosphonates. Onset of action 2-4 days. – Calcitonin. Rapid onset 2-4 Hours, peak effect in 48 hours, short lived effect. Dose 4-8 IU/Kg S.C Q12h. Works through inhibiting the effects of parathyroid hormones.

20. – Corticosteroids: only in steroid responsive tumours – Phosphate: rarely used for fear of soft tissue precipitations. – Cyclo - Oxygenase inhibitor: Indomethacin, rarely used if other drugs fail. – Dialysis: if renal failure is not improving with hydration and emerging volume overload.

21. Prevents bone resorption. Side Effects: Flu like symptoms, Nausea and vomiting 46%, Fatigue 39%, Fever 32%, Diarrhea 24%, Arthralgia/ myalgia 23%, and deterioration of renal function. Delayed onset of action 48 – 72h. 4mg IV infusion over 15 minutes following rehydration. May repeat after 7 days if not normo- calcemic and can tolerate hydration. Remember dose reduction based on creatinine clearance.

22. Denosumab: Fully human monoclonal antibody that targets and inhibits RANKL, a protein that acts as the primary signal to promote bone removal Indication: Prevention of skeletal-related events in patients with bone metastases from solid tumors Dose: 120 mg subcutaneously every 4 weeks Adverse events: Urinary and respiratory tract infections, cataracts, constipation, rashes, and joint pain Contraindications: Hypocalcemia. Patients should be taking calcium and vitamin D. No adjustment for hepatic or renal dysfunction is needed.

23. No Diuretics without Hydration in Hypercalcemia. Always check creatinine clearance and adjust doses, if using Bisphosphanates. Be aware about renal toxicity of Bisphosphanates and renal doses. Calcitonin lost its effect after 2-3 days. Review medications and stop agents, if feasible, that may cause hypercalcemia and/or renal impairment.

24. It’s a rapid development of metabolic abnormalities accompanying the release of intracellular contents into the bloodstream due to tumor cells death. Rapid release of intracellular contents can happen spontaneously with high tumor burden or from cell lysis due to cytotoxic agents (even steroids!), cytokine or hormonal therapy.

25. Aetiology:  A–Diseases: a –Leukemia - Acute and CLL b–Lymphoma - Burkitt’s- T- Cell- Lymphoblastic c –Solid tumor - Neuroblastoma- SCLC- Breast Cancer  B - Large tumor burden: - Stage IV extensive rapidly dividing tumors Precipitating Factors: - Spontaneous- Commencing treatment Co-factors: - Pre-existing renal insufficiency- hyperuricemia

26. Metabolic Abnormalities: Tumor cells contain a high concentration of potassium and phosphate. Their rapid breakdown will release these electrolytes into the blood resulting in: Hyperkalemia, Hyperuricaemia, Hyperphosphatemia and hypocalcaemia Soft tissue calcium phosphate deposition and hypocalcaemia occur as a result of calcium down- regulation secondary to Hyperphosphatemia Renal failure is a common complication.

27. Presentation : Many are asymptomatic Symptoms’ severity reflects the underlying metabolic abnormalities. 1- Hyperkalemia: life-threatening, ventricular dysrhythmias, paresthesia and weakness. 2- Hyperuricaemia: may lead to arthralgia and renal colic, urate nephropathy, fatigue, weakness etc… the worst ARF. 3- Hypocalcaemia: Neuromuscular instability with muscle cramps, tetany, anxiety, carpopedal spasms, bronchospasm, confusion and convulsions.

29. ARF in TLS

30. Management Prevention Once occurred ARF is a major problem with serious consequences.  Fix conditions that will make effects worse. NSAIDs  Get baseline labs: K, Ca, Phos, Uric Acid, LDH, Cr.  Preventing renal failure and severe electrolyte imbalances.  Increase urine production with proper hydration. (Competitive inhibitor of xanthine oxidase)  Decrease uric acid concentrations using Allopurinol (Competitive inhibitor of xanthine oxidase) which decrease uric acid synthesis from Purines but limited efficacy. Uric acid > 10x’s more soluble in pH of 7.0 compared to pH of 5.0  Alkalinize urine keeping PH above 6.5 as Uric acid > 10x’s more soluble in pH of 7.0 compared to pH of 5.0.

31. If occurred…. Continue the same measures Plus Manage ARF Magic Drug RASBURICASE Magic Drug RASBURICASE ( recombinant urate oxidase) promotes catabolism of uric acid  Allantoins (10x more soluble than uric acid).

32. What are the differences between Allopurinol and Rasburicase Oral versus IV Prevention and treatment Nephrotoxic Needs dose adjustment Fast action Drug - drug interactions Inhibits Enzymatic reactions or an enzyme Readily revert metabolic abnormalities including ARF Needs alkalinisation

33. Cord Compression

34. 2-5% of cancer patients have an episode of SCC Commoner in myeloma, prostate, lung and breast cancer (15-20%) 10% of patients diagnosed with SCC may have a second episode. Presentation Depends on level (77% in T spine). Radicular back pain in 85-95%. Worsened by lying flat, weight bearing, coughing and sneezing, relieved by sitting. Managed by Steroids, surgery and Radiation.

35. Methotrexate Toxicity Leucovorin Rescue ??? Methotrexate Toxicity. Factors that increase Methotrexate Toxicity: – Renal impairment – Third space fluid – Drugs e.g. penicillin, NSAIDS, PPIs etc. Safe Methotrexate level 0.05 – 0.1mM. Any MTX doses above 500 mg/m 2 needs rescue. Remember alkalinisation. Leucovorin and Fluorouracil???

36. Glucarpidase -A carboxypeptidase enzyme, is now approved and indicated for treating toxic methotrexate concentrations (greater than 1 μmol/L) in patients with delayed methotrexate clearance due to impaired renal function. -A single intravenous dose of 50 units/kg with Continue leucovorin until the methotrexate concentration has been maintained below the leucovorin treatment threshold for a minimum of 3 days. -However, caution must be used with administering leucovorin in conjunction with glucarpidase. -Leucovorin should not be administered within 2 hours before or after a dose of glucarpidase.

37. Case I A 20-year-old man was recently given a diagnosis of acute non–lymphocytic leukaemia. His white blood cell (WBC) count is 35 × 103 cells/mm3, and he will receive chemotherapy tomorrow. Which is the best prevention strategy for tumor lysis syndrome (TLS)?. A. Hydration with 5% dextrose (D5W), 1 L before chemotherapy, plus allopurinol 300 mg/day. B. Hydration with D5W, 100 mL/hour starting at least 24 hours before chemotherapy, plus allopurinol 300 mg/day. C. Normal saline 100 mL/hour starting at least 24 hours before chemotherapy plus allopurinol 300 mg/day. D. Hydration with normal saline 100 mL/hour starting at least 24 hours before chemotherapy plus NaCO3 500 mg orally every 6 H.

38. Case II A 65-year-old man with metastatic non–small cell lung cancer is brought to the clinic by his family because of alterations in his mental status. Pertinent laboratory values include a serum calcium concentration of 12 mg/dL and an albumin concentration of 2 g/dL. Which therapy is best for this patient’s altered mental status? A. Calcitonin 4 units/kg every 12 hours. B. Furosemide 20 mg orally. C. Dexamethasone 10 mg orally two times/day. D. Zoledronic acid 4 mg intravenously.