/Targeted Therapy Care through the years… Administration and Nursing Care in Pediatric and Adult Patents

Ramathibodi Cancer Center 28 June 2015

Colleen Nixon, MSN, RN, CPHON Hematology/Oncology Clinical Educator Boston Children's Hospital and Dana Farber Cancer Institute

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Cancer Treatments

Surgery (1850s‐present) Radiation (1899‐present)

Chemotherapy (1940s‐present) Biotherapy (1930s‐present)

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Cell Cycle Regulation Malignant cell growth

Regulation of movement through cell cycle Proto-Oncogene Transformation • Controlled by: • Oncogenes produce a perpetual signal for the cell to – Cyclins and cyclin‐dependent kinases (CDK) continually proceed through the cell cycle • Respond to checkpoints during cell cycle • Unrestricted cell growth and proliferation – G /S checkpoint 1 Tumor Suppressor Gene Loss • Also called restriction point (R) • Inability to inhibit cell growth and division • ensures cell ready for DNA synthesis Immortalization – G2/M checkpoint • ensures cell ready to enter the M (mitosis) phase and divide • Finite number of cell division Malignant cells lose control of cell proliferation • Inability to undergo • Continue through cell‐cycle and proliferate

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1 Question‐Clinical Trials Clinical Trials

Which response best describes the primary goal of a Phase III Today’s therapy is the result of 50 years of clinical trials ? • Identify patients who may need less therapy 1. Determine the efficacy of a new agent in the treatment of • specific types of cancer and to validate toxicity and dosage data. “Rearranging” the , the order and the dose • 2. Determine the value of a new agent in relation to existing Introduction of new therapy treatments • Earlier identification of who are going to fail therapy (before 3. Determine the maximum tolerated dose of an investigational relapse) drug or combination or using a recommended administration schedule and to identify dose limiting toxicities 4. Determine drug administration, acute toxicities and supportive care needs

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Components of Treatment Leukemia Chemotherapy Agents Chemotherapy Pediatric Adult /Plant Alkaloids//Miscellaneous/Alkylating Agents Anthrycycline: Anthrycycline: doxorubicin Plant Derivatives: Plant Derivatives: vincristine Biotherapy Antimetabolites: , Antimetabolites: methotrexate, CSFs/Cytokines//Monoclonal Antibodies , , mercaptopurine, cytarabine Alkylating Agents: Radiation High Risk Disease or CNS +

Surgery Central line placement

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Chemotherapy: Anthracyclines Chemotherapy: Plant Alkaloids

Doxorubicin Adverse Effects: cardiac arrhythmias, Vincristine Adverse Effects: local ulceration if N/V, vesicant, red tinged urine, ÏLFTs, • inhibitor • Cell cycle specific extravasated (vesicant), loss of deep alopecia, Ðblood counts, mucositis, tendon reflexes, jaw pain, constipation, LFT • • “M” phase specific Cell cycle specific: hepatotoxicity, radiation recall, changes, peripheral neuropathies. – S and late G 2 cardiomyopthy, secondary malignancies Rare: ptosis, vocal cord, paralysis, seizures, Nursing Considerations: tissue Nursing Considerations: good bowel damage if extravasation occurs, dose regimen, vesicant‐painful tissue damage if adjustments for renal or hepatic extravasation occurs, monitor LFTs, assess changes, monitor CBC & LFTs for foot drop before administeringÆ Special Considerations: must be given patient education for fall risk strategies with 30 min from start of Special Considerations: “Fatal if given (cardioprotectant agent) infusion. intrathecally; for IV use only."

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2 Chemotherapy: Antimetabolites Chemotherapy: Antimetabolites

Methotrexate Adverse effects: mucositis, N/V, Cytarabine Adverse effects: N/V, • Cell cycle specific, active myelosuppression • Cell cycle specific, active myelosuppression, diarrhea, rash, during during S phase flu‐like symptoms (fever, chills, generalized aches and pains), • Can be administered: IV, Nursing Considerations: ensure • Administered: IV, SC, IM, IT conjunctivitis, neuro changes PO, IM, IT adequate hydration and alkalinization, (dizziness, headache, nystagmus) use suntan lotion with at least SPF 30, avoid vitamins/foods with folic acid, Nursing Considerations: monitor hold sulfa drugs, aspirin and NSAIDS. CBC, neuro check before Monitor liver function tests. administration, steroid eye drops Administer leucovorin on time (HD cytarabine), effective regime.

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Chemotherapy: Antimetabolites Chemotherapy: Antimetabolites

Mercaptopurine Adverse effects: Mouth sores, skin (relapsed T‐cell) • Cell cycle specific, active rash, loss of appetite, diarrhea, Llow • Used in relapsed setting • Used in relapsed setting blood counts, abnormal LFTs during S phase Nursing Considerations: Nursing Considerations: • Administered PO Nursing Considerations: clear , neuro checks, good premedicate with antiemetics, administration guidelines: may take bowel regimen, monitor LFTs, monitor for TLS, monitor LFTs, with water, but not with assess for peripheral symptom relief for rash any other food or liquid. Take at neuropathy; provide education Adverse Effects: TLS night, preferably at bedtime. Give at for fall risk strategies myelosuppression, hepatic least 2 hours after food or any liquid Adverse Effects: Low blood veno‐occlusive disease, or except water. After each dose, no counts, N/V, fatigue, (VOD), N/V, headache, food or liquid (except water) for at neurotoxicity, peripheral diarrhea, rash least 1 hour (preferably longer) neuropathy

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Chemotherapy: Miscellaneous Agents Chemotherapy: Miscellaneous Agents

Cortiocosteroids: Adverse Effects: personality Peg‐ or Adverse Effects: allergic reaction, prednisone, dexamethasone, changes, pancreatitis, gastritis, Erwinia asparaginase thrombosis, pancreatitis, N/V, poor methylprednisolone hyperglycemia, hypertension, • Cell‐cycle non‐specific appetitie, Ï blood sugar • Cell‐cycle non‐specific immunosuppression, muscle • Depletes from weakness, acne, alteration in sleep leukemia cells; inhibits Nursing Considerations: observe x (w/dexamethasone) cataracts protein synthesis 60 min after administration; Nursing Considerations: emergency meds available; monitor administer with food or GI bili & LFTs in adults protection, anticipatory guidance about behavior, nutrition & sleep Administered IV or IM patterns, taper after long‐term use

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3 Chemotherapy: Alkylating Agents Immune System & Biological Therapy

Cyclophosphamide Adverse Effects: anorexia, • Cell‐cycle nonspecific N/V, Ð blood counts, alopecia, • Cause DNA strand breaks gonadal dysfunction or sterility, SIADH, metallic taste, hemorrhagic cystitis

Nursing Considerations: monitor S.G., urine heme, ensure 1‐2cc/kg/hr UOP, +/‐ mesna

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Types of Immunotherapy Question‐Immunotherapy History

Immunotherapy for oncology includes: Whose research formed the • Cytokines basis for the current use of – Hematopoietic Growth Factors cytokines? A. Dr. Daniel F. Felton • Monoclonal Antibodies (MoAB) B. Dr. Sidney Farber • Angiogenesis C. Dr. William B. Coley • Tyrosine Kinase Inhibitors (TKI) D. Dr. Murdock Equen • Chimeric Antigen Receptor Therapy (CAR‐T) • Therapeutic • Gene therapy • Cancer—killing viruses

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Immunotherapy: Monoclonal Immunotherapy: Growth Factors Antibodies (MoAB) Action Indication Side Effects Filgrastim/Neulasta Stimulates neutrophil ÐWBC bone pain, joint pain, growth & enhances fever, rash, pain or neutrophil activity redness at injection site

Sargramostin Stimulates bone ÐWBC after SCT headache, malaise, marrow to produce fatigue, rash, puritis, neutrophils & bone pain, myalgia, macrophages fever, chills Erythropoietin/Darbop Stimulates the division ÐRBC hypertension, fever, oetin & differentiation of headaches, myalgia, erthrocyte stem cells rash, redness @ injection site Oprelvekin Stimulates ÐPlatelets Swelling (hands & feet), megakaryocyte N/V, SOB, mouth sores, precursors & diarrhea, headache megakaryocyte MoAB maturation

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4 Immunotherapy: Types of MoAB MoAB: Targeting specific proteins

Trigger the immune system: Agent Mechanism of Action Target • Rituximab (Rituxan) Rituximab Antibody to CD‐20 B‐ALL • Ofatumumab Blinatumomab Attach patient’s CD‐3 T B‐ALL Block signals to tell cancer to divide cells to CD‐19 • Epratuzumab Epratuzumab Antibody to CD‐22 B‐ALL • Moxetumomab Inotuzumab Antibody to CD‐22 B‐ALL Carry cancer drugs or radiation to cells: Combotox Antibody to CD‐19 & 22 B‐ALL • Gemtuzumab ozogamicin Moxetumomab Antibody to CD‐22 B‐ALL • Inotuzumab Ozogamicin Alemtuzumab Antibody to CD‐52 B & T‐ALL Ofatumumab Antibody to CD‐20 B‐ALL

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Immunotherapy: Rituximab Blinatumomab Classification & Adverse Effects Nursing Considerations Action Rituximab Monoclonal Common: fever, chills, Continuous cardiac monitoring antibody rigors, rash during infusion. Pre‐med with acetaminophen & Anti CD20; binds to Occasional: diphenhydramine; IV steroid if CD20 antigen on B‐ anaphylaxis; hypoxia, previous reaction to rituximab cell lymphocytes; hypotension, TLS, • If hypersensitivity develops, resulting in cell acute renal failure, stop the infusion. Administer death mucositis supportive care & for symptoms. If symptoms CD20 is expressed have resolved, the infusion rate on the blast cells of may be resumed at a slower 40‐50% of patients rate; all subsequent infusions with B‐cell ALL the maximum rate should not exceed the previously tolerated rate. Blinatumomab

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Question‐Monoclonal Antibodies Question‐Angiogenesis History

Rituximab is directed against which antigen: Who was the first scientist to hypothesize that if a tumor could A. GD2 be stopped from growing it’s own blood supply, the tumor would B. CD20 shrink and die? C. CD52 A. Dr. Sidney Farber D. CD33 B. Dr. Elizabeth Blackwell C. Dr. Judah Folkman D. Dr. Hugh D. Rioden

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5 Angiogenesis Inhibitors VEGF Signaling Pathway

• Dependent on angiogenesis • Blood vessel growth by secreting growth factors, including Tumor Viability Vascular Endothelial Growth Factor (VEGF)

•VEGF leads to signaling cascade in endothelial cells • Production of factors that stimulate vessel permeability, Tumor Viability proliferation, migration and differentiation into mature bld cells

•Prevent tumor from developing new blood vessels VEGF •Agents do not kill cancer cells Inhibitor

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Tyrosine Kinase Inhibitors (Avastin®) (TKIs) Adverse Effects: hand‐foot • Prevents VEGF from Adverse Effects: Hypertension, fever, Imatinib‐Administer each skin reaction, diarrhea, alopecia, weight loss, rash, infusional reactions, proteinuria, dose with a meal and a large binding to receptors hypertension, rash, decreased chills, hypokalemia, N/V, diarrhea, glass of water to reduce GI • Inhibits VEGR induced appetite, stomatitis, nausea, Ðblood counts, GI bleeding irritation. angiogenesis pruritus, and abdominal pain. Nursing Considerations: close monitoring during infusion, monitor Sorafenib Take without food, Nursing Considerations: s/s GI perforation, monitor for wound 1 hour before or 2 hours after reduce friction and heat healing complications, antiemetics prn a meal; at the same times exposure to your hands and Pediatric indications: refractory or every day feet for about 1 wk after metastatic solid tumors treatment

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BCR‐ABL Immunotherapy‐CAR‐T

Klebanoff,, C., Yamamoto, T. & . Restifo, N. Immunotherapy: Treatment of aggressive with anti‐CD19 CAR T cells. Nature Reviews Clinical Oncology 11, 685–686, (2014), doi:10.1038/nrclinonc.2014.190. Published online: November 2014

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6 Challenges and the future… References

• Early identification of patients who are going to fail therapy • Asselin, B. L. Gaynon, P. & Whitlock, J. A. (2013). Recent advances in acute • lymphoblastic leukemia in children and adolescents: An expert panel Identifying patients who may be cured with less therapy discussion. Current Opinion in Oncology, 25 (3), S1‐S16. • Emphasis on risk based therapy • Ettinger, A. G. & Rae, M.L. (2011). Chemotherapy: Agents and classifications. In – ↓late effects N. Kline (Ed.), The Pediatric Chemotherapy and Biotherapy Curriculum, 3rd edition, (pp. 45‐71). • Targeted therapy is much more specific and less toxic • Gainer, L. (2010). Biological and targeted therapies. In D. Tomlinson & N. Kline • Conventional chemotherapy alone is not going to change (Eds.), Pediatric Oncology Nursing, 2nd edition, (pp.283‐294). survival rates • Kline, N. (Eds). (2014). Childhood Cancer Treatment. Essentials of Pediatric • AYA should be treatede lik children Hematology/Oncology Nursing, 4th edition, Chicago: Association of Pediatric Hematology/Oncology Nurses, pp. 111‐195). (at least with ALL) • Marrs, J. & Zubal, B.(2009). Oncology nursing in a new era: Optimizing treatment with Bevacizumab. Clin Journal of Oncology Nursing 13(5), 564‐572.

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References (continued) • Mathisen, M. S., Kantarjian, H.& Jabour, E.(2014). Emerging drugs for acute lymphocytic leukemia. Expert Opinion Emerging Drugs, 19(1), 37‐50. • McCarthy, K. (2014). Leukemia. In N. Kline (Ed.), Essentials of Pediatric Hematology/Oncology Nursing, 4th edition, Chicago: Association of Pediatric Hematology/Oncology Nurses, pp. 25‐32. • National Cancer Institute (2006). Biological Therapies for Cancer. Retrieved April 13, 2015, from http://www.cancer.gov/cancertopics/treatment/types/immunotherapy/bio‐ therapies‐fact‐she • Wilkes, G. (2009). Intravenous administration of antineoplastic drugs. Journal of Infusion Nursing, 32 (5): 276‐285. • Wills, M. (2011). Cancer research. In N. Kline (Ed.), The Pediatric Chemotherapy and Biotherapy Curriculum, 3rd edition, (pp. 23‐25). • Wood, W. A. & Lee, S. J. (2011). Malignant hematologic diseases in adolescents and young adults. Blood, 117, (22), 5803‐5815.

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