Nursing Pharmacology Chapter 33-34:  Anticancer Drugs

• Natural Products: 

  • Topoisomerase Inhibitors Type II: Epirubicin (Ellence)

    • Overview:

      • Epirubicin is an isomer of doxorubicin characterized by increased lipophilicity.⁷ 

      • Epirubicin belongs to the anthracycline class of anticancer drugs, inhibiting DNA and RNA synthesis following intercalation between DNA pairs.⁹ 

        • Intercalation between base pairs induces DNA cleavage (mediated by topoisomerase II) and as a consequence cell death.

        • Epirubicin exhibits antineoplastic effects at any stage of the cell cycle.

        • This agent is approved as adjuvant treatment for breast cancer in those patients exhibiting axillary node involvement.⁹

          • Although first approved in this adjuvant setting (early-stage, node -positive breast cancer), epirubicin is also employed in both metastatic breast cancer therapy and gastroesophageal cancer.³

           

          • Epirubicin and Cyclophosphamide before Doxcetaxel in Early Breast Cancer¹¹

            Attribution: Ejlertsen B Epirubicin and cyclophosphamide before doxcetaxel in early breast cancer.  https://www.youtube.com/watch?v=QlzwQTwQvIs (1/2017) ecancer Youtube Channel:  https://www.youtube.com/channel/UCGb_Xmf5mzvyXC7NOjsonkg

           

          • Should Anthracyclines Be Given in Advanced Gastroesophageal Cancer?¹²

            Attribution: Bendell J Chau I Janjigian Y Shah M Should Anthracyclines Be Given in Advanced Gastroesophageal Cancer.https://www.youtube.com/watch?v=tCqeV6xbs-k (11/2016) OncLiveTV Yourtube Channel:  https://www.youtube.com/channel/UC3aRpa3CR_w4JrxYv_r_pDg

    • Absorption, Distribution, Biotransformation, Excretion:

      • Epirubicin is administered by the intravenous (IV) route of administration.⁹ 

      • The drug exhibits a volume of distribution (Vd) of about 24 L/kg with protein binding of about 80% (albumin).

      • Epirubicin undergoes substantial hepatic and extrahepatic metabolism.⁹  

      • As noted by the volume of distribution, epirubicin is substantially distributed in tissue.¹⁰ 

      • Drug elimination is mainly biliary (<15% of epirubicin is found in the urine).¹⁰ 

        • Epirubicin metabolism involves conversion to metabolites that are either mainly or completely inactive.

        • Some of these metabolites include a 13-dihydro derivative, epirubicinol, 2 glucuronides and 4 aglycones.

        • Epirubicin glucuronides and epirubicinol metabolites describe a unique metabolic pathway in humans which may account for improved drug tolerance when compared with doxorubicin.

          • A 3-compartment model describes epirubicin pharmacokinetics.

          • The median half-life associated with these compartments (phases) are about 3 minutes, 1 hour and 32 hours.¹⁰

    • Toxicity: 

      • Epirubicin toxicity is the same as that described earlier for doxorubicin.⁷

        • Doxorubicin Toxicities

          Acute toxicities associated with doxorubicin administration include: Myelosuppression Alopecia Mucositis G.I. disturbances (nausea/vomiting). The acute, dose-limiting toxicity is myelosuppression. Antiemetic drugs are administered along with doxorubicin. Antiemetic drugs that may be helpful in managing acute emesis associated with chemotherapeutic agents, such as doxorubicin, which are classified as having a high "emetic risk." (Navari RM Management of Nausea and Vomiting June 1, 2015;(https://www.cancernetwork.com/cancer-management/management-nausea-and-vomiting) Antiemetic Agents:   Chemotherapy-Induced Emesis13 Granisetron (Sustol, Sancuso) Ondansetron (Zofran, Zuplenz) Palonosetron (Aloxi) Dexamethosone (Ozurdex et al) Metochlopramide (Reglan)  Haloperidol (Haldol) Dronabinol (Syndros, Marinol) Nabilone (Cesamet) Prochlorperazine (Compro) Lorazepam (Atavan) Natupitant (Akyneo [natupitant + palonosetron]) Aprepitant/Fosaprepitant. Pro-drug  (Emend) Extended infusion time reduces both nausea and likelihood of cardiotoxicity. As noted above, doxorubicin is a significant vesicant and following extravasation significant skin necrosis may occur. Accordingly, infusions through a central venous catheter is likely appropriate. Acute and Chronic Toxicities:8 Anthracycline Cardiotoxicity14 Attribution: Russell, III, R Antracycline Cardiotoxicity:  The Role of Cardio-Oncology in Management https://www.youtube.com/watch?v=cpfeGjTCT20 (9/2012; published 3/2018) Yale Cancer Center Youtube Channel:  https://www.youtube.com/channel/UClDVKSccJn3qHFnmkCxgHPQ Cardiotoxicity is both an acute and chronic associated with doxorubicin administration. Cardiac toxicity may occur even though the drug remains effective in tumor treatment. Cardiotoxicity may occur associated with anthracycline-based anticancer agents given alone or in combination with other chemotherapy. Furthermore, cardiotoxicity is also associated with the monoclonal anticancer antibody, trastuzumab (Herceptin). The combination of anthracycline and trastuzumab, in patients with tumors expressing high HER2/neu levels, is contraindicated due to enhancement of anthracycline -related cardiac damage by trastuzumab.  Use of doxorubicin in treating children is particularly problematic given increased pediatric patients sensitivity to cardiotoxic effects.8 Acute cardiotoxicity due to doxorubicin clinically presents usually as arrhythmias which may include heart block. Most serious presentations are described by a pericarditis-myocarditis syndrome characterized by: Fever Pericarditis and CHF (congestive heart failure). This serious,acute side effect may be fatal and could occur even with low, cumulative doxorubicin doses.  Chronic cardiotoxicity occurs due to cumulative myocardial damage.8  Myocyte pathology involves both myofiber disruption and cytoplasmic reticulum dilation. In latter stages, a "diffuse myocardial fibrosis" may be observed. This pathology is likely unique to anthracycline anticancer agents allowing for differential diagnosis (versus ischemic myocardial damage or viral cardiomyopathy). Anthracycline-caused cardiotoxicity often presents with typical CHF symptoms such as: Cough Weight gain Peripheral edema and in some more severe cases, Pulmonary edema(severe cases). Risk factors for anthracycline-caused cardiotoxicity include: Female gender Concurrent or previous chest radiation Cardiac comorbidity Age. CHF associated with doxorubicin administration is often treatable using usual CHF therapies, such as diuresis.8 Secondary Leukemia:7,8 Another late-onset doxorubicin (as well as other anthracyclines) toxicity is secondary leukemia. The side effect is likely due to balanced chromosomal translocations due to topoisomerase II "poisoning." The risk level of secondary acute myeloid leukemia (AML) is about 2% or less. In those clinical settings in which the likelihood of cure is high, the risk of a secondary leukemia is and especially important consideration, such as in the pediatric setting or in anthracycline drug administration as adjuvant treatment for breast cancer.7,8

    • Clinical Uses:

      • Although first approved in this adjuvant setting (early-stage, node -positive breast cancer), epirubicin is also employed in both metastatic breast cancer therapy and gastroesophageal cancer.³