Adverse Effect of Cytostatic

Indwiani Astuti Dept of Pharmacology & Therapy Fac of Medicine Universitas Gadjah Mada Yogyakarta
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Learning Objectives
Identify the adverse effect of Cytostatic especially abdominal complain To know how to minimizing the side effects of Cytostatic

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Introduction
Cytostatic /cytostatic/ (stah-statik) 1. suppressing the growth and multiplication of cells. any substance that inhibits cell growth and division

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What are cytostatic drugs?

The word cytostatic describes the way some anti-cancer drugs work. Most drugs that are used to treat cancer kill the cancer cells. The word 'cytotoxic' means toxic to cells, or cell-killing. Chemotherapy is properly called 'cytotoxic therapy'. There are other treatments that do not kill cancer cells. They work by stopping the cancer cells from multiplying. So, they stop the cancer growing. For example, hormone therapies used to treat breast cancer could also be called cytostatic therapy.
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 The treatment can be physically exhausting for the patient. Current chemotherapeutic techniques have a range of side effects mainly affecting the fast-dividing cells of the body.

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Tumour selectivity of chemotherapy

Most drugs used in cytostatic chemotherapy interfere with the synthesis of DNA and /or RNA, with the results that cell death occurs or cell multiplication ceases. These effects are not confined to malignant cells cytostatic agents are also toxic to normal dividing cells, particularly those in bone marrow, the GIT, gonads, hair folicles and skin (rapidly dividing cells).

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Narrow therapeutic index/toxic side effects

1. 2. 3. 4. 5. 6. 7. 8. Bone marrow suppression Mucositis throughout GI tract Febrile neutropenia, increased risk of infection Alopecia Nausea, vomiting and cachexia Damage to reproductive system Neurotoxicity DNA damage treatment can be mutagenic, carcinogenic and teratogenic
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Incidence of Chemotherapy-Induced Nausea and Vomiting (CINV) and Pain in Cancer Patients
Approximately 70%80% of chemotherapy patients experience nausea and vomiting1 Patients rank nausea and vomiting as 2 of the most feared side effects of cancer treatment More than three quarters of cancer patients experience chronic pain during the course of their disease2

1. Wiser W, Berger A. Oncology. 2005;19:637. 1/11/2011 2. Portenoy RK. Semin Oncol. 1995;22(suppl 3):112.

Consequences of Unresolved CINV

Adverse sequelae of nausea and vomiting in the cancer patient
Serious metabolic derangements Nutritional depletion and anorexia Esophageal tears Wound dehiscence Deterioration of patients physical and mental status Degeneration of self-care and functional ability Discontinuation of therapy

1/11/2011 NCCN Practice Guidelines in OncologyVersion 1. 2007. Antiemesis, MS-1.

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Emetogenic Potential of Antineoplastic agents

Navari RM. Pathogenesis-based treatment of chemotherapy induced nausea and vomiting Two new agents. J Support Oncol 2003;1:89-103

Patient-Specific Risk Factors for CINV

Age <50 years Women > men History of light alcohol use History of vomiting with prior exposure to chemotherapeutic agents Other risks History of motion sickness History of nausea or vomiting during pregnancy History of anxiety

ASHP. Am J Health Syst Pharm. 1999:56:729-764; Balfour and Goa. Drugs. 1997:54:273-298.

Types of CINV
Acute CINV: Nausea and vomiting with in the first 24 hrs of chemotherapy Delayed CINV: After 24 hrs lasting up to 5 days Anticipatory CINV: After a negative past experience with chemotherapy Breakthrough CINV: Occurs despite patient being treated with preventive therapy Refractory CINV: Occur during subsequent cycles of

chemotherapy when antiemetic prophylaxis has failed in earlier

cycles

Pathophysiology of CINV
Cerebral cortex
Cancer chemotherapy Smell Sight Thought Anticipatory emesis

Chemoreceptor Trigger Zone (CTZ)

(Outside BBB) Dopamine 5 HT, substance P

Vomiting Centre (medulla)

Ach, 5 HT Histamine & Substance P Chemo & radio therapy

Pharynx & GIT

5 HT & Substance P

Pathophysiology of Chemotherapy-Induced Emesis

Causes of Nausea and Vomiting in Cancer Patients

Gastric stasis Drugs
Opioids Chemotherapy

Biochemical
Hypercalcemia Uremia

Raised intracranial pressure Intestinal obstruction Pain

1/11/2011 Twycross R. Palliative Care. 3rd ed, Radcliffe Medical Press. Oxford:1999:114.

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NCCN (National Comprehensive Cancer Network) Practice Guidelines Prechemotherapy Emesis Prevention
Highly emetogenic regimens Day 1: aprepitant, dexamethasone, and a 5-HT3 antagonist +/- lorazepam May be modified on days 24 Moderately emetogenic regimens Day 1: dexamethasone and a 5-HT3 antagonist +/- lorazepam (aprepitant added with select moderately emetogenic regimens) Modified on days 24 Low emetogenic regimens Dexamethasone, proclorperazine, or metoclopramide +/- lorazepam

1/11/2011 NCCN Practice Guidelines in Oncology Version 1. 2007. Antiemesis, MS-1.

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NCCN Practice Guidelines Postchemotherapy/Delayed Emesis Prevention Highly emetogenic regimens

Primary antiemetic regimen continued through period when delayed emesis may occur (ie, 23 days after chemotherapy cycle)

Moderately emetogenic regimens

Dependent upon the antiemetic used before chemotherapy
Palonosetron on day 1 only Aprepitant continued on days 2 and 3 +/- dexamethasone or lorazepam Dexamethasone or a 5-HT3 antagonist +/- lorazepam

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NCCN Practice Guidelines Breakthrough Treatment

Around-the-clock administration, rather than PRN dosing, should be considered Additional agents should be from a different drug class than initial therapy
Possibilities include: dopamine antagonists, metoclopramide, butyrophenones, cannabinoids, corticosteroids, or agents such as lorazepam

Nabilone (cannabinoid) has recently been approved for nausea/vomiting in patients who have not responded to conventional antiemetics
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National Comprehensive Cancer Network(NCCN) Guidelines

High Emetic Risk Chemotherapy- Emesis prevention

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Moderate Emetic Risk Chemotherapy- Emesis prevention

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Neurotransmitter Sites For Nausea

Muscarinic Dopaminergic Histamine Serotonin (5HT-3) Neurokinin 1 (NK 1) Cannabinoids
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Diverse Neurotransmitters Mediate Emesis

Serotonin (5-HT3) Dopamine (D2)

Histamine

Substance P (NK-1)

N+V REFLEX

Endorphins

GABA Cannabinoids

Acetylcholine

Drug classes FDA approved in CINV Adapted from Andrews PL, Naylor RJ, Joss RA. Supportive Care Cancer. 1998;6:197-203. 1/11/2011 25

Serotonin Receptor Inhibitors (5HT3)

Granisetron (Kytril) Dolasetron (Anzemet) Ondansetron (Zofran) Palonosetron (Aloxi) : Benefit of longer duration of action 2-5 days after treatment Best used as a cocktail with steroid (dexamethasone) and lorazepam
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Serotonin Receptor Inhibitors: Common Side Effects

Headache Constipation
Prevent with use of laxatives and stool softeners

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NK 1 Receptor Inhibitor
Aprepitant (Emend) Used for acute and delayed nausea in combination with a serotonin receptor-blocking drug

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Dose Schedule

Ondan 32mg iv Apre 20 125mg Dexa mg oral

Ondan 32mg iv
Dexa 12 mg oral Days 1 2 2 Apre 80mg 3 4 5 5 6 6 7 7

Days 1

3 4 Dexa 8mg b d Dexa 8mg

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Indications and Dose

FDA approved on March 2003 for prevention of acute and delayed CINV with single or repeated courses of highly emetogeneic chemotherapy 125 mg on day 1 (before chemotherapy) and then 80mg on days 2 and 3(after chemotherapy) Should be given with a 5HT3 antagonist and dexamethsone Dose of dexamethasone should be reduced by 50%

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Cannabinoids
Botanical
Marijuana Hashish

Endogenous
Anandamide 2-AG PEA

Pharmaceutical

Nabilone Dronabinol Delta-9-THC & cannabidiol

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Cannabinoid Receptors
CB1neuromodulation CB2immunomodulation

Basal ganglia
Hippocampus Cerebral cortex Cerebellum Spinal cord Afferent nociceptors

Spleen
Tonsil Mast cells Macrophages Lymphocytes Microglia

1/11/2011 Kalant H. Pain Res Manag. 2001;6:80.

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Mechanism of Action of the Cannabinoids

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EXOGENOUS Cannabinoid Therapy

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Neurotransmitter (NT) from presynaptic neuron activates the postsynaptic neuron Activated postsynaptic neuron releases endocannabinoids Endogenous CB1 ligand diffuses back to and binds to the presynaptic CB1 receptor CB1 receptor activates a G-protein, leading to inhibition of NT release

Presynaptic Neuron

Inhibition of Neurotransmitter Release

CB1 Receptor

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Postsynaptic Neuron

Neurotransmitter Receptor

Endogenous Cannabinoid Retrograde Signaling

Endogenous and Exogenous Cannabinoids Reduce Neuronal Signaling

Nabilone is thought to activate CB1 receptors directly, mimicking the effects of endocannabinoids
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1/11/2011 Adapted from Page 5 of Slatkin NE. J Support Oncol. 2007;5(suppl3):1. Reprinted with permission.

CannabinoidsSupportive Oncology
Established roles
CINV

Emerging roles
Analgesia Spasmolysis Anorexia-cachexia Sedative Antidepressant Antineoplastic

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Dopamine Antagonists
Phenothiazines Prochlorperazine (Compazine) Metoclopramide (Reglan) Trimethobenzamide (Tigan) Limited role except for mildly
emetogenic drugs and may be helpful

in delayed nausea
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Delayed Nausea
Dexamethasone Lorazepam (Ativan) Dopamine antagonists
Prochlorperazine (Compazine) Trimethobenzamide (Tigan)

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Mucositis (Mouth Sores)

More common with certain drugs:
5-fluorouracil (5-FU) Methotrexate Doxorubicin (Adriamycin) Cyclophosphamide (Cytoxan)

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Mucositis (Mouth Sores)

Prevention Icing of the mouth during treatment Treatment Options Gel Clear Magic Mouthwash Viscous lidocaine
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Diarrhea
Major toxicity of several drugs used to treat gastrointestinal cancers, for example, 5-FU and irinotecan (Camptosar)
Acute diarrheal reaction to irinotecan
Atropine at time of treatment
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Delayed Diarrhea: Treatment

Anti-Motility Drugs Loperamide (Imodium) Diphenoxylate (Lomotil)
Octreotide (Sandostatin) Somatostatin analogue Works to prolong GI transit time Subcutaneous administration
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Diarrhea: Changes in Diet

Increased fluid intake Increased starch content

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Hand-Foot Syndrome
Pain, redness, swelling, and peeling of the skin of the palms and soles Associated with certain agents

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Capecitabine (Xeloda) Liposomal doxorubicin (Doxil) Infusional 5-FU Weekly taxane therapy
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Hand-Foot Syndrome: Treatment Options

Dose reduction Avoid tight-fitting shoes; repetitive rubbing or prolonged heat to hands and feet Emollients
Eucerin Bag Balm Can be used effectively with cotton socks and/or gloves at bedtime
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Fatigue: Multifactorial
Anemia
Erythropoietin (Procrit)/darbepoetin (Aranesp)

Depression
Selective serotonin reuptake inhibitor (SSRI)

Sleep Disturbance
-- Sleep aid: zolpidem tartrate (Ambien), eszopiclone (Lunesta)

Psychostimulants
-- Methylphenidate (Ritalin)
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Neuropathy
Painful burning sensation Progressive numbness Motor weakness

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Neuropathy
Acute, cold induced Oxaliplatin (Eloxatin) Chronic, dose related Oxaliplatin Taxanes
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Neuropathy: Prevention
Avoidance of cold exposure for 48-72 hours after oxaliplatin therapy Amino acid therapy (glutamine) Vitamin B6 (pyridoxine)

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Neuropathy: Treatment Options

Dose reduction Gabapentin (Neurontin) Amitriptyline (Elavil)

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Support Therapy
A.
B. C. D. E.

Filgrastim (Neupogen)
Granulocyte colony-stimulating factor, prophylaxis of chemotherapy-induced neutropenia Granulocyte/macrophage colony-stimulating factor, aids neutrophil recovery in AML patients Prevents hypercalcemia and bone resorption associated with malignancy Stimulates bone marrow RBC production, treats anemia resulting from myelosuppressive therapy Folate supplement
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Sargramostim (Leukine) Pamidronate (Aredia) Erythopoietin (Procrit) & Darbopoiten Leucovorin

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Targeted Cancer Therapy The dream of the Magic Bullet

Side Effect-Free Cure of Cancer

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