ADR chemotherapy for nurse student .pptx

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1. ADR of Chemotherapeutic Agents and Management Abinet Abebe (B.Pharm, MSc in Clinical Pharmacy) Department of Clinical Pharmacy and Pharmacy Practice School of Pharmacy, CHMS, Mizan Tepi University 1

2. Cytotoxic , targeted anticancer and immunotherapy agents are toxic to cancer cells and also to various host tissues and organs. The adverse effects of anticancer therapies can be classified as common and acute toxicities , specific organ toxicities , and long-term complications. Common and acute toxicities generally occur as a result of inhibition of host-cell division. 2

3. Host tissues most susceptible to cytotoxic agents include tissues with renewal cell populations , such as lymphoid tissues, bone marrow, and epithelium of the GI tract and skin. Some other common and acute toxicities (e.g., nausea and vomiting, hypersensitivity reactions) frequently occur in patients shortly after therapy. Specific organ toxicities often are attributed to a unique uptake or a selective toxicity of the anticancer agent to the organ. 3

4. Long-term complications are toxicities that occur months to years after anticancer therapy. These long-term toxicities occur secondary to continued immunodeficiencies or from permanent damage to the organ cells from the specific therapy Clinicians should also be aware of patient-specific factors, such as the stage of disease , concomitant illnesses , and concurrent medications, which could cause signs or symptoms that mimic the adverse effects associated with anticancer therapy 4

5. Common and acute toxicities Myelosuppression Myelosuppression continues to be one of the most common dose limiting side effects with chemotherapeutic agents. Chemotherapy regimen(mostly commonly carboplatin and Paclitaxel ) significantly affect any cell line, including RBCs, neutrophil, and platelets & cause morbidity or mortality. Decreased RBCs can cause anemia, low neutrophil counts significantly increases a patient’s risk for bacterial infections and reduced platelets can cause thrombocytopenia , 5

6. Neutrophils and platelets are usually affected first because they have life spans measured in hours to days. Red blood cells have a lifespan of about 3 months, so they are among the last cell lines affected by chemotherapy. The timeline for myelosuppression is varied, but generally occur within 7 to 10 days and recover within 14 to 26 days. Agents such as carmustine, lomustine, and mitomycin C have: delayed effect on bone marrow occurring in 4 to 6 weeks. 6

7. Drugs that cause bone marrow suppression 7

8. Neutropenia Febrile Neutropenia: Definition Fever: Single oral temperature ≥38.3°C or persistent temperature ≥38.0 °C for >1 hour and Neutropenia: ANC <500, or ANC <1000 and a predicted decline to <500 over next 48 hrs, ANC = WBC x % granulocytes (segs plus bands) Neutropenic fever is a medical emergency requiring initial intervention in the emergency room. Fever is commonly the only symptom 8

9. Prevention of Neutropenia Reduce ( by 25%) dose of each agent for all subsequent cycles. But , it can also compromise the response and survival of patients with chemotherapy sensitive tumors Prophylactic administration of CSFs can be used to reduce myelosuppressive effects of cytotoxic chemotherapy. Several CSFs- G-CSFs [filgrastim, filgrastim- sndz ]), and a pegylated long-acting form of filgrastim, pegfilgrastim are avaialable 9

10. The recommended initial dose of filgrastim, tbo -filgrastim or filgrastim- sndz , is 5 mcg/kg/day as a single daily subcutaneous (SC) injection beginning 24 to 72 hours following the administration of myelotoxic chemotherapy. 10

11. Treatment of Neutropenic Fever Febrile neutropenia leads to increased hospital admissions and lengths of stay as well as greater morbidity and mortality Colony Stimulating Factors (CSF): mainly indicated as prophylaxis but, also indicated for treatment of neutropenic fever to reduce duration of neutropenia Not routinely used for neutropenic fever unless the patient had previous history of neutropenic fever with prior chemo cycle. 11

12. Not shown to decrease mortality, but used in neutropenic septic shock/severe sepsis (hypotension, organ dysfunction) The G-CSF-receptor is present on precursor cells in the bone marrow, when stimulated by G-CSF initiates proliferation and differentiation into mature granulocytes. Peg-filgrastim: daily SC dosing: 6 mg, 24 hrs after chemo and single dose is as effective as 11 days of G-CSF 5 mcg/kg Peg-filgrastim vs Filgrastim , which one is preferred? 12

13. Before empiric antibiotic therapy, infection accounted for 75% of all mortality among patients receiving chemotherapy Early studies showed a 70% increase in mortality with a delay in administration of empiric antibiotics once neutropenic fever was identified 13

14. Management of Febrile Neutropenia 14

15. Thrombocytopenia A reduction in platelet count is another common myelosuppressive toxicity seen with chemotherapy. Increased risk of bleeding occurs when platelet count significantly decreased especially, less than 20,000/mm3 which requires platelet transfusion Most commonly, thrombocytopenia is managed via the use of platelet transfusions and modifications to the chemo dosing 15

16. Drugs cause Thrombocytopenia 16

17. Treatment Observation/careful watchfulness if platelet count is above 20,000/mm3 Dose reduction/modification of regimen Glucocorticoids Platelet Transfusion In patients are unresponsive to GCs: IV Ig will usually increase platelet count to a safe level in 1-3 days. 17

18. Transfusion Mostly transfusion is not considered until the patient is symptomatic: ecchymosis, petechiae or hemoptysis It is the most common way to treat thrombocytopenia associated with cancer and chemotherapy The goal is to prevent or stop bleeding, but temporarily correct thrombocytopenia and are associated with complications The benefits should outweigh the risk of transfusion. 18

19. Complications of Platelet Transfusion: Allergic reactions to life-threatening anaphylaxis Febrile reactions (1%) Infectious complications: bacterial, viral, parasitic 19

20. Oprelvekin A platelet growth factor produced in E.coli by rDNA Directly stimulates the proliferation of hematopoietic stem cells and megakaryocyte progenitor cells, and induces megakaryocyte maturation. Prevent severe thrombocytopenia and reduce the need for platelet transfusions after myelosuppressive chemotherapy. Dose:50 mcg/kg/day initiated 6-24 hours after completion of chemotherapy 20

21. Continue until a platelet count of >50,000 cells/mm is reached Dosing beyond 21 days is not recommended Most common ADR includes: Edema, shortness of breath, tachycardia, and conjunctival redness Use with caution in Patients with a history of heart failure or atrial arrhythmias Romiplostim ???? 21

22. Anemia Anemia is most common hematologic complication of chemotherapy, but is not a dose-limiting toxicity Chemotherapy predominantly affects RBCs by causing anisocytosis and macrocytosis. These effects are related to inhibition of DNA synthesis , and they predominantly occur after treatment with antimetabolites, including folic acid analogs, hydroxyurea, purine antagonists, and pyrimidine antagonists 22

23. Erythropoiesis stimulating agents (ESAs) Can be given to increase red cell production/ hemoglobin and reduce/ avoid transfusions in patients They aren't proven to increase quality of life, improve anemia symptoms. ESA starting dose:– 40,000 units of epoetin alpha given subcutaneously once per week as a single dose, Weekly dosing: 60,000 units Outcome: Hgb increase by >1 g/dL per week 23

24. Darbepoetin Sarting dose of 500 mcg once every three weeks , but weekly or biweekly dosing can be used Response Rate Only about 50% of patients respond to ESAs Patients not respond within 8 to 12 weeks should stop therapy. 24

25. Criteria to initatate ESAs: Patients should have symptomatic chemo-induced anemia Rule out other causes of the anemia Hemoglobin level is <10 g/ dL prior to therapy. Rule out patients with uncontrolled hypertension 25

26. Monitor Serum iron, TIBC, and serum ferritin in all anemic chemotherapy patients who are considered for an ESA and in patients who fail to respond to therapy within six to eight weeks. In addition, when needed, IV iron should be given during therapy with erythropoietin to keep the transferrin saturation >20% and the serum ferritin level >100 ng/ mL. 26

27. Thrombotic Events The risk of thrombosis markedly elevated in cancer patients. Possible mechanisms include:-abnormalities in clotting factors, vessel wall damage, vessel wall compression by tumor masses. Risk factors include: type and stage of cancer, comorbidities, mobility, and type of systemic anticancer therapy received. Pancreatic, stomach, kidney, lung, brain, and uterine cancers are associated with the highest risk. 27

28. Use of systemic anticancer therapy has been associated with a 2.2 fold increased risk of thrombosis Several anticancer agents have been associated with an increased thrombosis risk, including cytotoxic chemotherapy (cisplatin, fluorouracil), hormonal targets (tamoxifen, aromatase inhibitors), antiangiogenic therapies (bevacizumab) Prophylaxis : low-molecular-weight heparin or warfarin 28

29. Gastrointestinal Tract Toxicities The GI tract, second only to bone marrow in its susceptibility to toxic effects produced by cytotoxic chemotherapy. GI toxicities include nausea and vomiting, oral complications, esophagitis, and lower bowel disturbances 29

30. Nausea and Vomiting Nausea and vomiting are common and serious toxicities associated with many cytotoxic and targeted anticancer agents Significant reductions in quality-of-life scores have been demonstrated in cancer patients with CINV compared with patients who did not have those symptoms Five distinct types of CINV have been defined: acute, delayed, anticipatory, breakthrough and refractory. Recognizing the differences between these types of CINV has important implications for both prevention and management. 30

31. Acute emesis   Emesis occur with in the first 24 hours after chemotherapy. Begins within 1-2 hours and peaks in the first 4-6 hours. Most widely studied manifestation of CINV. Delayed emesis  Emesis occur more than 24 hours after chemotherapy Peaks at 48 to 72 hours, subsides over next 2-3 days Less f requency and episodes of emesis compared with acute emesis, it is less controlled with antiemetic medications 31

32. Anticipatory emesis   Conditioned response in patients who have developed during the previous cycles of chemotherapy. Can be elicited by a variety of stimuli and cognitive activities in association with subsequent cycles of chemotherapy Less significant with improved antiemetic control during the initial cycle of chemotherapy 32

33. Breakthrough CINV can be defined as nausea and/or vomiting that occurs within 5 days of chemotherapy treatment despite the use of a guideline-recommended antiemetic protocol, which requires the addition of more agents referred to as “ rescue medications” “ Olanzapine  and  metoclopramide” Refractory CINV can be described as nausea and/or vomiting that consistently occurs in subsequent chemotherapy cycles despite the use of a guideline-recommended antiemetic regimen 33

34. Classification of CINV 34

35. The pathophysiologic mechanism of CINV D rugs activate neurotransmitter receptors in the small intestine; then afferent fibers transmit the stimuli to the brainstem , which then sends out efferent signals via the vagus nerve to induce vomiting. Several areas in the central and peripheral nervous systems and gastrointestinal tract are involved in CINV Three areas in the brainstem are thought to play critical roles in the emetic reflex : vomiting center and two areas in dorsal brainstem called nucleus tractus solitarius and area postrema 35

36. The major neurotransmitter receptors associated with the emetic response include serotonin (5-HT3), neurokinin 1 (NK1) and dopamine receptors. Other receptors involved include corticosteroid, acetylcholine, histamine, cannabinoid, gabaminergic, and opiate receptors. Many of these receptors are targets for antiemetic therapy 36

37. Risk Factors Patient Factors Poor control during the previous cycles Gender…… Female Age …… Young Alcohol ……. Possible protective role History of N/V during pregnancy and H istory of motion sickness Drug related factors E metogenic potential of combination agents Intrinsic emetogenicity of the chemotherapy agent Route and rate of administration, as well as the dose 37

38. Based on the percentage of patients vomiting at least one time in 24 hrs after chemotherapy, chemotherapy agents were placed into four categories:- High – >90% risk of emesis Anthracycline/cyclophosphamide, Carmustine, Cisplatin, Cyclophosphamide ≥1500 mg/m 2, Dacarbazine Moderate – >30 to 90% risk of emesis, Carboplatin, Cyclophosphamide <1500 mg/m 2 Cytarabine >1000 mg/m 2, Daunorubicin*,Doxorubicin, Ifosfamide Irinotecan, Oxaliplatin 38

39. Low – 10 to 30% risk of emesis, Cytarabine ≤1000 mg/m 2, Docetaxel, Eribulin, Etoposide, Fluorouracil, Gemcitabine, Ipilimumab, Ixabepilone, Methotrexate, Mitomycin Minimal – <10% risk of emesis, Bevacizumab, Bleomycin, Vinblastine, Vincristine 39

40. Pharmacotherapy of CINV Prevention and treatment of CINV is based on its subtype. The primary goal is to prevent CINV from occurring so that subsequent episodes of nausea and vomiting and the potential for anticipatory CINV are avoided. Uncontrolled nausea and vomiting have potential effects on the patient’s QOL and adherence to chemotherapy Emesis control should be individualized to patient need and, depending on the chemotherapeutic agents used, duration of regimen, the route of administration for the antiemetic, and considerations regarding the AEs of the antiemetic agents 40

41. Management : anti emetic agents by pharmacologic class 41

42. Serotonin (5-HT3) Receptor Antagonists Ondasterone the first in the class The most widely used antiemetic drugs in chemotherapy. Dolasetron ( Anzemet ) Granisetron ( Kytril ) Ondansetron (Zofran) Palonosetron ( Aloxi ) 42 The first-generation 5-HT3 receptor antagonists, ondansetron , dolasetron, and granisetron, with half-lives between 3 and 9 hours The second-generation compound in this class, palonosetron , has a half-life of approximately 40 hours Differences in half-lives influence dosing and possibly indication, Ondansetron, dolasetron, and granisetron are most commonly used in acute CINV , Palonosetron demonstrates efficacy in delayed CINV

43. Mechanism……Block serotonine receptors peripheral antagonism of receptors in the GI and central antagonism of receptors in the medulla(CTZ) ADR …Headache and constipation (10-15 %) Ondansetron and dolasetron….. Caution in long QT syndrome All of them have………….. similar efficacy 43

44. Sancuso® Patches New options for preventing CINV, a PATCH version of granisetron Long acting: works up to 7 days Ideal for patients getting up to 5 consecutive days of chemo Apply it to upper arm at least 24 hours BEFORE the first chemo session and leave it on for at least 24 hours AFTER the last session. 44

45. Palonosetron Half-life ~ 40 hrs Dose- 0.25 mg IV push 30 min before Chemo on day 1 of each cycle or 1 capsule an hour before chemo starts It is useful for preventing delayed nausea and vomiting because it works longer than other oral 5-HT3 antagonists. Intravenous palonosetron is also approved for post-op nausea . 45

46. Aprepitant Neurokinin-1 receptor antagonist – Substance P blocker Approved for use in combination with other antiemetics in case of high dose of cisplatin Increase efficacy by 20% when added to 5HT3 plus dexamethasone regimen Only available as PO Fosaprepitant 150 mg IV (single dose) Netupitant , is formulated with palonosetron , in a fixed-dose combination for acute and delayed CINV. 46

47. Other agents Dexamethasone is the corticosteroid of choice for CINV , used in combination with other agents to increase antiemetic efficacy in acute and delayed CINV. Dexamethasone may also be used as monotherapy in low–emetic risk chemotherapy regimens Dopamine receptor antagonists ( eg , metoclopramide, prochlorperazine) were used in early attempts to alleviate CINV. Olanzapine used particularly for breakthrough CINV Benzodiazepines are most often used in treating anticipatory CINV , also included in regimens to treat breakthrough or refractory CINV Cannabinoids, ginger, behavioral t reatments……alternatives Rx ?????? 47

48. Treatment Protocol For patients receiving highly emetogenic chemotherapy anthracycline and cyclophosphamide (AC) regimen The three-drug combination of: NK1 receptor antagonist (days 1-3 for aprepitant, day 1 only for fosaprepitant) a 5-HT3 receptor antagonist (day 1 only), and Dexamethasone (days 1 through 3 or 1 to 4) 48

49. Dose IV Ondansetron 32 mg or granisetron 1 mg or dolasetron 100 mg on day 1 plus Aprepitant 125 mg plus dexamethasone 12 mg PO on day 1 aprpepitant 80 mg PO plus dexamethasone 8 mg PO ……..on days 2 and 3, and dexamethasone 8 mg PO on day 4. ADR: LFT’s and BUN (transient) 49

50. Moderately Emetogenic Antineoplastic Agents The two-drug combination of: Palonosetron (day 1 only) and Dexamethasone (days 1 through 3) If palonosetron is not available: first generation 5-HT3 receptor antagonist, preferably granisetron or ondansetron Limited evidence of benefit of adding aprepitant to the combination. Low Emetogenic Antineoplastic Agents A single 8-mg dose of dexamethasone before chemotherapy Minimal risk…….no routine prophylaxis 50

51. Drugs that are considered to be lower therapeutic index Cannabinoids antiemetics, Metoclopramide, butyrophenones (droperidol, haloperidol), and phenothiazines (prochloperazine, chlorpromazine) . Place in Therapy: These drugs should not be used first-line for chemoinduced nausea and vomiting should be reserved for those intolerant or refractory to first-line agents 51

52. Mucositis Inflammation and ulceration of the inside of the mouth, esophagus, and lower GI tract Can cause pain and infection. Cells in the GI tract turnover rapidly, making them a target for chemotherapy. It can also result in: weight loss and dehydration due to the pain associated with eating and drinking . 52

53. Some patients will become NPO and require intravenous nutrition. Signs and symptoms usually start: about 5 to 7 days after chemo or at any time during radiation therapy. Explain to patients the importance of oral saline rinses and good oral hygiene during therapy especially if they're taking bleomycin, cytarabine, fluorouracil, doxorubicin, high dose etoposide, or methotrexate. 53

54. Patients on Fluorouracil may benefit from holding ice chips in their mouth for 30 minutes around the time of drug administration. Lesions usually lessen and disappear completely in about 1 to 3 weeks or when white blood cell counts recover. 54

55. Palifermin The only agent approved for the prevention of mucositis and it's only indicated in patients on high dose chemotherapy prior to stem cell transplantation. It is a human recombinant keratinocyte growth factor (KGF) designed to regrow the mucosal layers. It's dosed at 60 mcg/kg by IV infusion once daily for 3 days before and 3 days after chemo. 55

56. Its side effects include rash, itching, redness, and taste disorders. Twice daily chlorhexidine rinses can be tried for prevention, but not all studies have shown a benefit. Patients who develop mucositis should be encouraged to use saline rinses multiple times per day 56

57. Viscous lidocaine, dyclonine, or compounded mouthwash may help with the pain If mucositis persists, some patients may require intravenous pain control with PCAs. 57

58. Caphosol (supersaturated calcium phosphate rinse) Is another alternative used to provide relief for mucositis as well as xerostomia. C an be given orally as a swish and spit 2 to 10 times daily. 58

59. Treatments for the oral candida infections that can occur include: oral nystatin or clotrimazole troches. Systemic antifungal ( fluconazole, etc) usually aren't necessary. 59

60. Diarrhea Diarrhea is another problem often encountered in chemotherapy It is most commonly seen with: irinotecan, etoposide, cetuximab , erlotinib , lapatinib , sunitinib , high-dose cytarabine, and fluorouracil. With irinotecan : – patients can experience a cholinergic effect during and soon after the infusion that can necessitate the need for 0.4 to 1 mg of IV atropine. 60

61. Milder cases may respond to loperamide or bile acid sequestrant cholestyramine Severe cases may require octreotide , electrolytes, antibiotics, and IV hydration . Regimens containing agents like irinotecan and fluorouracil concomitantly can be very problematic. 61

62. Hair Loss Hair loss due to chemotherapy can be the most upsetting side effect for patients. And it's not just hair on the head that can be lost. Total body alopecia can occur, especially with taxanes 62

63. The good news is that hair grows back once chemo stops. Hair loss usually starts about 1 to 2 weeks after a cycle of chemo. Usually, hair will start growing back 1 to 2 months after chemotherapy is complete. Often the hair that grows back after chemo is a different texture or may be somewhat lighter or darker in color. Hair loss is psychologically devastating to some patients, especially teenagers. 63

64. Fertility Radiation can significantly impact the female reproductive tract causing irreversible damage to the ovaries and loss of the menstrual cycle. Makes the uterus more difficult to attain and maintain pregnancy. In men radiation can cause testicular damage. Sperm counts may return to normal over a year or two or they may stay low, especially in men who've received high dose radiation to the area. 64

65. Alkylating agents are: especially likely to cause amenorrhea in women and absent or prolonged low sperm counts in men. Men and women who desire children after chemotherapy or radiation are often counseled to freeze eggs and sperm in advance. And it's usually suggested that women wait at least 6 months after their last chemo cycle before trying to conceive 65

66. Secondary Malignancy Cancer treatments can also cause other cancers later in life . Treatment with alkylating agents, teniposide, etoposide, or anthracyclines is more likely to result in secondary cancers. The most common types of secondary cancers are myelo dysplastic syndrome and acute myeloid leukemia. 66

67. Radiation therapy can also result in: breast cancer and sarcomas later in life, especially the radiation used for Hodgkin's disease. Radiation induced malignancy is significant in pediatric patients that receive high doses early in life. 67

68. Extravasation Some cancer chemotherapy agents can cause severe damage when they are accidently administered outside a vein. These are so called vesicants e.g : Anthracyclines, mitomycin C, nitrogen mustards, and the vinca alkaloids. The taxanes can also cause significant tissue damage. 68

69. Damage can include sloughing of the skin, loss of mobility, tissue necrosis, and even loss of a limb. If pain occurs and an infusion is still running, it should immediately be stopped and any fluid aspirated out of injection site. 69

70. For most extravasations cold compresses should be applied the exception is vinca alkaloids where heat should be applied. The involved area should be outlined and watched for signs of infection. To be safe all vesicants should be administered through a central line. 70

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