Pharmacotherapy of Cancer

Cancer
A cellular disorder, clonal origin Progressive accumulation of a mass of cells Progressive invasion of surrounding tissues and organs Ability to metastasize to distant organs

Cancer
Essentially, a genetic disease Mutation of genes:

Oncogenes Tumor suppressor genes Mismatch repair genes

Germline mutation: hereditary or familial cancer Somatic mutation: sporadic cancer

Cellular Kinetics
Human body contains 5x1013 cells

Cells can either be non dividing and terminally differentiated continually proliferating but may be recruited into cell cycle

- rest

Tumour becomes clinically detectable when there is a mass of 109 cells (1g)

The Cell Cycle

Tumor kinetic
Growth rate depends on:

growth fraction
-percent of proliferating cells within a given system -human malignacy ranges from 20-70% -bone marrow 30 %

cell cycle time

-time required for tumour to double in size

rate of cell loss

Tumor Kinetics Original Hypothesis

Conventional views in the field of oncology support the notion that:

tumor growth is exponential chemotherapy treatment is designed to kill in log intervals (kills constant fractions of tumor)
Combination therapy and increased drug dose levels aim at improving ovarian cancer chemotherapy.

Gompertzian Growth
Growth rates are exponential at early stages of development and slower at later stages of development.

- Biological growth follows this characteristic curve.

Gompertzian growth model

Initial tumour growth is first order, with later growth being much slower

Smaller tumour grows slowly but large % of cell dividing

Medium size tumour grows more quickly but with smaller growth fraction

Large tumour has small growth rate and growth fraction

Tumor Growth
number of cancer cells

10 12

10 9

diagnostic threshold (1cm)

time

undetectable cancer

detectable cancer host death

limit of clinical detection

Rationales in Human Cancers

Small tumors grow faster than larger tumors Human cancers grow by non-exponential Gompertzian kinetics

Principle of chemotherapy
First order cell kill theory

- a given dose of drug kills a constant percentage of tumour cells rather than an absolute number

Maximum kill Broad coverage of cell resistance

Hypothesis of Alternative Intervals

The rate of tumor volume regression is proportional to the rate of growth.

Tumors given less time to grow in between treatments are more likely to be destroyed.

Tumor cell regrowth can be prevented if tumor cells are eradicated using a denser dose rate of cytotoxic therapy.

Principle of chemotherapy
Rationale for combination chemotherapy
Different drugs exert their effect through different mechanisms and at different stages of the cell cycle, thus maximize cell kill Decease the chance of drug resistance

Paraneoplastic syndrome
Syndrome
Systemic

Clinical manifestation
anorexia, cachexia, weight loss, fever hypercalcemia, hyponatremia, hypoglycemia, syndrome digital clubbing,

Endocrine
Cushing Skeletal / connective tissue pulmonary osteoarthropathy Neurolgic / muscular

hypertrophic

myasthenia gravis, Eaton-Lambert syndrome, polymyositis, peripheral neuropathy, subacute cerebellar degeneration

Paraneoplastic syndrome
Syndrome

Clinical manifestation
anemia, polycythemia, leukocytosis, thrombocytosis, deep vein thrombosis dermatomyositis, acanthosis nigricans nephrotic syndrome, glomerulonephritis

Hematologic

Skin Renal

Psychosocial effects of cancer

Loss of control Fear of pain and mutilation Separation and loneliness

The Changing Nature of Palliative Care

CURATIVE CARE

PALLIATIVE CARE

CURATIVE CARE PALLIATIVE CARE

TIME

AIM OF COMBINATION THERAPY

INCREASED EFFICACY

ACTIVITY
Different mechanisms of action Different mechanisms of resistance

SAFETY
Compatible side effects

It is easy to kill cancer cells, but the challenge is keeping the patient alive at the same time..!

How to treat cancer

Clinical evaluation and treatment options 1. Diagnosis: pathological diagnosis 2. Evaluation of disease: staging 3. Treatment objectives: curative, palliative 4. Treatment options 5. Evaluation of response 6. Supportive therapy

Modalities of treatment
Local treatment options Surgery Radiation Systemic treatment options Chemotherapy Hormonal therapy Biotherapy Molecular-targeted therapy

Principle of Treatment :
Most anticancer treatment is directed towards killing actively dividing cells.

Complications: Marrow aplasia, alopecia, sterility, GIT, lung, kidney damage).

Newer drugs target tumor cells by immune mechanisms or hormones.

General Disease-Related Consequences of Cancer

Impaired immune and hematopoietic function Altered gastrointestinal structure and function

Motor and sensory deficits

Decreased respiratory function

Karnofsky Performance Scales

Chemotherapy
Treating cancer with chemical agents Major role in cancer therapy Used to cure and increase survival time Some selectivity for killing cancer cells over normal cells Normal cells most affected: the skin, hair, intestinal tissues, spermatocytes, and blood-forming cells

Chemotherapy Drugs
Antimetabolites Antitumor antibodies Alkylating agents Antimitotic agents Topoisomerase inhibitors Miscellaneous chemotherapeutic agents Combination chemotherapy

Treatment Issues
Drug dosage Drug schedule Drug administration

Route : IV, IM, SC, IT Extravasation Vesicants

Side Effects of Chemotherapy

Alopecia or hair loss Nausea and vomiting Mucositis in the entire gastrointestinal tract Skin changes Anxiety, sleep disturbance Altered bowel elimination Decreased mobility Hematopoietic system changes Bone marrow suppression Hypersensitivity (esp. taxanes, platinums)

Immunotherapy: Biological Response Modifiers

Drugs that modify the clients biologic responses to tumor cells Cytokines: enhance the immune system Interleukins, interferons Side effects: generalized and sometimes severe inflammatory reactions, peripheral neuropathy, skin rashes, increased depression

Gene Therapy
Experimental as a cancer treatment Renders tumor cells more susceptible to damage or death by other treatments Injection into tumor cells, enabling the immune system to better recognize cancer cells as foreign and kill them Antisense drugs

Targeted Therapies
Definition New technology and drugs that allow the cancer treatment to target a certain cancer cell by interfering with the natural functions of tumor growth How they work They target specific parts of a cancer cell or its actions; hand in a glove analogy What it means in cancer treatment Potentially fewer side effects

Targeted Therapies
Monoclonal antibodies: proteins that trigger the bodys pathways involved in cancer growth to fight cancer more effectively.

EGFR: family of receptors found on surface of normal and cancer cells that bind with an epidermal growth factor (EGF) causing cells to divide.

Tyrosine Kinase Inhibitors: Part of the cell that signals it to divide and multiply; enhances cell growth. Still investigational

Vaccines: stimulate the bodys immune system to fight the cancer

Role of Chemotherapy in Cancer Treatment

Adjuvant chemotherapy

a short course of combination chemotherapy in a patient with no evidence of residual cancer after surgery or radiotherapy, given with the intent of destroying a small number of residual tumor cells

Neoadjuvant
chemotherapy given in the preoperative or perioperative period

Primary:
same as neoadjuvant chemotherapy, also applied to chemotherapy given in the absence of intended surgery or radiotherapy

Salvage:
-combination chemotherapy given in a patient who has failed or recurred following a different curative regimen

Palliative:
chemotherapy given to control symptoms or prolong life in a patient in whom cure is unlikely

Induction: combination chemotherapy given with the intent of inducing complete remission when initiating a curative regimen

Consolidation: repetition of the induction regimen in a patient who has achieved a complete remission after induction

Intensification: chemotherapy after complete remission with higher doses, with the intent of increasing the cure rate or remission duration

Maintenance: long-term, low-dose chemotherapy in a patient who has achieved a complete remission

Clinical Endpoints in Evaluating Response to Chemotherapy

Objective Response Complete Response (CR) Partial Response (PR) Progressive Disease (PD) Stable Disease (SD)

Measurable disease (longest diameter)

Relapse-free survival after stopping treatment (>= 4 wks)

At least a 50% reduction in measurable tumor mass

> 25% increase in one or more lesions

Neither PR nor PD (no changes)

Tumor which are Curable with Chemotherapy : in advanced disease

Choriocarcinoma Wilms tumor Embryonal Acute leukemia rhabdomyosarcoma Hodgkins disease High grade non-Hodgkins Ewings sarcoma lymphoma Neuroblastoma Germ cell tumor Small cell lung cancer Ovarian cancer

Neoadjuvant chemotherapy
Preservation of the tumor mass as a biologic marker of responsiveness to the drugs

Sparing of vital normal organs

Chemotherapy has Minor Activity

Brain tumor (astrocytoma) Cervical cancer Colorectal cancer Non small cell lung cancer

Melanoma Pancreatic cancer Prostate cancer Soft tissue sarcoma Hepatoma Renal cell carcinoma

CHEMOTHERAPEUTIC AGENT :CLASSIFICATION

Alkylating agents:

mechlorethamine, busulfan, nitrosoureas, cyclophosphamide, chlorambucil, melphalan

Antimetabolites:
methotrexate, 5-fluorouracil, nucleoside analogues

Anthracyclines:
doxorubicin, epirubicin

Antimicrotubule agents:

vinca alkaloids, taxanes

Platinum analogues:
cisplatin, carboplatin

Topoisomerase II inhibitors:

etoposide, tenoposide

Topoisomerase I inhibitors: camptothecins Antibiotics: bleomycin, dactinomycin

Types of chemotherapy

Cell cycle dependent

Cell cycle phase specific

Cell cycle independent

Cell cycle phase non-specific

Sites of Action of Cytotoxic Agents Cell Cycle Level

Antibiotics
Antimetabolites
S (2-6h)

G2 (2-32h) M (0.5-2h)

Vinca alkaloids
Mitotic inhibitors

Taxoids
Alkylating agents

G1 (2-h) G0

Cycle-Specific Agents

Sites of Action of Cytotoxic Agents Cellular Level

DNA synthesis Antimetabolites

DNA

Alkylating agents

DNA transcription

DNA duplication

Intercalating agents

Mitosis

Spindle poisons & Microtuble Stablizers

ALKYLATING AGENTS

Cyclophosphamide

alkylation of DNA through the formation of reactive intermediates oral bioavailability 100% T1/2 3-10 hrs -- parent compound, 8.7 hrs -phosphoramide mustard metabolism:
microsomal hydroxylation hydrolysis to phosphoramide mustard (active) and acrolein

Metabolism of Cyclophosphamide
CYCLOPHOSPHAMIDE
HEPATIC CYTOCHROMES P 450

ACTIVATION

INACTIVATION
4-KETOCYCLOPHOSPHAMIDE CARBOXYPHOSPHAMIDE
ALDEHYDE DEHYDROGENASE

4-OH CYCLOPHOSPHAMIDE

ALDOPHOSPHAMIDE

ACROLEIN

PHOSPHORAMIDE MUSTARD

TOXICITY

CYTOTOXICITY

Cyclophosphamide

toxicity:
myelosuppression alopecia pulmonary fibrosis Intake daytime pill cystitis: use MESNA with high-dose therapy SIADH cardiac toxicity leukemogenesis infertility teratogenesis

MESNA = 2-mercaptoethane sulfonate Na (Na = sodium), used as chemother

ANTIMETABOLITES

Methotrexate (MTX)

inhibition of dihydrofolate reductase--->partial depletion of reduced folates polyglutamates of MTX and dihydrofolate inhibit purine and thymidylate biosynthesis metabolism: converted to polyglutamates in normal and malignant tissues elimination: primarily as intact drug in urine, third-space retention

Methotrexate (MTX)

High dose toxicity: rescue by leucovorin Pretreatment with MTX increases 5-FU and ara-C nucleotide formation NSAIDs decrease renal clearance and increase toxicity Reduce dose in proportion to decrease in creatinine clearance NO high-dose MTX to patients with abnormal renal function Monitor plasma conc. of drug and hydrate patients during highdose therapy

Methotrexate (MTX)

toxicity: myelosuppression mucositis renal tubular obstruction and injury in high-dose therapy, requires urine alkalinization and hydration hepatotoxicity in chronic therapy pneumonitis hypersensitivity: rare neurotoxicity

5-fluorouracil (5-FU)

Interferes with RNA synthesis and function inhibition of thymidylate synthase (TS) Affect DNA stability primary T1/2 8-14 min, clearance is faster with infusional schedules, non-linear pharmacokinetics 90% is eliminated by metabolism, <10% unchanged drug renally excreted, dihydropyrimidine dehydrogenase (DPD)

5-FU

Leucovorin increases activity and toxicity Toxicity: GI epithelial ulceration myelosuppression skin toxicity ocular toxicity neurotoxicity cardiac toxicity biliary sclerosis (hepatic arterial infusion of FUDR)

Cytidine analogues Cytosine arabinoside (araC) 2-2-difluoro-deoxycytidine (gemcitabine)

AraC
inhibits DNA polymerase alpha short plasma T1/2 elimination: deamination in liver, plasma and peripheral tissue 100% blocks DNA repair, enhances activity of alkylating agents

AraC

toxicity: myelosuppression
GI epithelial ulceration intrahepatic cholestasis, pancreatitis cerebellar and cerebral dysfunction (highrenal function) conjuctivitis (high-dose) hidradenitis noncardiogenic pulmonary edema

dose, elderly, impaired

ANTHRACYCLINES

Pleiotropic effects:

Inhibition of dna topoisomerase ii activity Activation of protein kinase c, Generation of reactive oxygen and stimulation of apoptosis

Doxorubicin: protein binding 60-70% Elimination: 50-60% by hepatic aldo-keto reductase

Drug clearance is decreased in the presence of hyperbilirubinemia or patients with marked burden of metastatic tumor in liver

Heparin binds to doxorubicin causing aggregation Toxicity:

Myelosuppression

Mucositis
Alopecia Cardiac toxicity: acute and chronic, cumulative dose-related (hypertensive heart disease, mediastinal) Severe local tissue damage after drug extravasation

Radiation sensitization of normal tissue

ANTIMICROTUBULE AGENTS
Vinca alkaloids: vincristine, vinblastine, vinorelbine Taxanes: paclitaxel, docetaxel Vinca alkaloids
Inhibit polymerization of tubulin Hepatic metabolism and biliary excretion Patients with abnormal liver function test should be treated with caution

Vinca alkaloids

toxicity: Neutropenia except vincristine thrombocytopenia (vinblastine)

Peripheral neuropathy (capping of vincristine to 2.0 mg) jaw pain

Constipation

SIADH (vincristine, vinblastine)

Taxanes (paclitaxel, docetaxel)

High-affinity binding to microtubules, Stabilize microtubules against depolymerization, Inhibit mitosis Elimination: predominantly by hepatic hydroxylation (p450 enzyme) and biliary excretion of metabolites, less than 10% eliminated intact in urine Dose should be modified in patients with abnormal liver function test

Paclitaxel & Docetaxel

1971
Pacific Yew: Taxus brevifolia
OH

1986
European Yew: Taxus baccata

Taxanes:
Toxicity: acute hypersensitivity reactions, premedication with corticosteroid and antihistamines (h1 and h2 blockers) neutropenia, thrombocytopenia mucositis (esp. prolonged infusion, 96-hr) alopecia sensory neuropathy cardiac conduction disturbances fluid retention (docetaxel)

PLATINUM ANALOGUES
Cisplatin, carboplatin, oxaliplatin

Cisplatin
Covalent binding to DNA Inactivated by sulfhydryl groups, covalently binds to glutathione, metallothioneins, and sulfhydryls on proteins 25% is excreted during the first 24 hrs, renal > 90%, bile < 10%

Cisplatin
toxicity: renal insufficiency with Mg2+ wasting, monitor electrolytes, Mg2+, Ca2+, use with caution in the presence of other nephrotoxic drugs

nausea and vomiting peripheral neuropathy auditory impairment myelosuppression visual disturbance (rare) hypersensitivity (rare) seizures (rare)

Carboplatin
drug is primarily excreted, only a small fraction is metabolized 90% excreted in urine in 24 hrs toxicity: myelosuppression, esp. thrombocytopenia nausea and vomiting nephrotoxicity at high doses and in patients with prior renal dysfuction reduce dose in proportion to reductions in creatinine clearance

Oxaliplatin
Greater distribution to tissue than cisplatin (50 times) Excrete by urine in metabolite form Never reconstitute in 0.9% NaCl (unstable) Toxicities :
neurotoxic peripheral sensory neuropathy N/V/D

TOPOISOMERASE II INHIBITORS
Etoposide
Inhibition of DNA topoisomerase II Terminal t1/2 6-8 hrs Hepatic metabolism, renal excretion 35-40% Reduced dose proportionate to creatinine clearance
Toxicity: neutropenia, thrombocytopenia (mild), alopecia hypersensitivity, mucositis (high doses)

CAMPTOTHECINS
Irinotecan (CPT-11) Topotecan Irinotecan
inhibit topoisomerase I by stabilizing the cleavable complex in which the enzyme is covalently bound to DNA at a single-stranded break site is a prodrug which requires enzymatic cleavage by the carboxylesterase converting enzyme to generate the biologically active metabolite, SN-38

Irinotecan
elimination: 22% is excreted unchanged in the urine, the rest by biliary excretion and conversion to SN-38 toxicity: diarrhea- early onset within hours or during the infusion associated with cramping, vomiting, flushing and diaphoresis, controlled by atropine. late-onset diarrhea can occur later than 12 hours following drug administration, may be controlled by high-dose loperamide (an initial dose of 4 mg followed by 2 mg every 2 hours or 4 mg every 4 hours during the night)

Irinotecan

toxicity: myelosuppression, neutropenia

alopecia nausea and vomiting mucositis fatigue elevated liver function, caution in patients with liver dysfunction pulmanary toxicity (uncommon) associated with a reticulonodular infiltrate, fever, dyspnea, and eosinophilia

ANTIBIOTICS
Bleomycin, dactinomycin

Bleomycin
Oxidative cleavage of DNA initiated by hydrogen abstraction Metabolism: activated by microsomal reduction and degraded by hydrolase found in multiple tissues Elemination: renal 45-70% in first 24 hrs

Bleomycin
Reduce dose for creatinine clearance < 60 ml/min Toxicity: pulmonary interstitial infiltrates and fibrosis, increased risk in patients with underlying pulmonary disease, age > 70, renal insufficiency, prior chest radiation, oxygen during surgery, cisplatin desquamation, esp of fingers and elbows Reynaud phenomenon hypersensitivity reaction (fever, anaphylaxis, eosinophilic pulmonary infiltrates)

Dactinomycin (actinomycin D)
Inhibition of RNA and protein synthesis Elimination: renal 6-30%, bile 5-11% Avoid extravasation: necrosis Toxicity: myelosuppression nausea and vomiting mucositis diarrhea radiation sensitization and recall reactions

PROPHYLACTIC AGENTS

Antiemetic regimens:

Acute emesis: serotonin antagonist + dexamethasone or metoclopramide (1 mg/kg) + dexamethasone Delayed emesis: (cisplatin, carboplatin, doxorubicin, high dose cyclophosphamide): metoclopramide 0.5 mg/kg IV/PO QID x 24 d (8-16 doses) then every 4 hrs PRN Dexamethasone 4-8 mg IV/PO x 4 d Diphenhydramine 50 mg PO every 4 hrs, PRN only for restlessness or acute dystonic reactions

Hydration: cisplatin, ifosfamide, high dose methotrexate

Premedications for paclitaxel: (prevent hypersensitive reaction)

dexamethasone 20 mg PO 12 and 6 hrs prior to paclitaxel 20 mg IV 30-60 min prior to paclitaxel diphenhydramine 50 mg IV/PO 30-60 min prior to paclitaxel cimetidine 300 mg or ranitidine 50 mg IV 30-60 min prior to paclitaxel

Growth factors: G-CSF for prophylaxis in previous febrile neutropenia or high incidence of grade IV neutropenia

MESNA

Prevention of Ifosfamide-induced hemorrhagic cystitis Prevention of high-dose cyclophosphamide-induced hemorrhagic cystitis

Dosage calculation in oncology

Body surface area

derived in 1916 by Du Bois and Du Bois reduce the interpatient variability of drug exposure and, hence, drug effects

AUC (carboplatin) Fix dosing

Dose (mg) = Target AUC (mg/mL/min) x [GFR (mL/min) + 25]

Body surface area calculation: Nomogram

Managing Cancer Treatment Side Effects and Toxicity

SIDE EFFECTS OF CHEMOTHERAPY

Mucositis Alopecia

Pulmonary fibrosis Nausea/vomiting Diarrhea Cystitis Sterility Myalgia Neuropathy Local reaction Renal failure Myelosuppression Cardiotoxicity

Phlebitis

Irritant vs. Vesicant

Local inflammatory reaction Intact blood return Short-term injury

Bleomycin Platinum Doxorubicin (both forms) Etoposide Ifosfamide

Infiltrating surrounding tissue blistering May be delayed 6-12 hr Severe necrosis Absent of blood return

Anthracyclins Vinca alkaloids Teniposide Streptozocin

Extravasation of Cytotoxic drug

Port-a-cath
Port inserted in vein for chemotherapy A Port B Catheter [tubing] C Subclavian vein D Superior Vena cava E Pulmonary vein F Aorta G Heart

Side Effects of Chemotherapy

Alopecia or hair loss Nausea and vomiting Mucositis in the entire gastrointestinal tract Skin changes Anxiety, sleep disturbance Altered bowel elimination Decreased mobility Hematopoietic system changes Bone marrow suppression Hypersensitivity (esp. taxanes, platinums)

Alopecia (hair loss)

Anthracyclins Etoposide Irinotecan (Campto) Cyclophosphamide Taxanes Ifosphamide Vindesine Vinorelbine Topotecan

Alopecia (hair loss)

2-3 days after within a few weeks 3-6 months regain after stopping treatment baldness may be temporary, partial or total Tx

Cold cap Wig

Cancer-induced nausea and vomitting

Etiology of Nausea and Vomiting in Patients with Cancer

Direct Treatment Related: chemotherapy
- acute - delayed - anticipatory - breakthrough N/V - refractory N/V
Indirect Treatment Related: mucositis opiates anti-infectives gastroparesis infection hyperacidity anorexia diarrhea pain anxiety

radiation therapy prophylactic antibiotics

Etiologies of Nausea and Vomiting in Oncology Patients

Chemical (chemotherapy-induced: acute and delayed; opioids)

Vestibular

CNS (increased intracranial pressure)

Visceral (direct disease-related sources, abdominal irradiation)

Proposed Pathways for ChemotherapyInduced Nausea and Vomiting (CINV)

Higher CNS centers

Chemoreceptor trigger zone Chemotherapy

Medulla oblongata

Vomiting center
Increased afferent input to the chemoreceptor trigger zone and vomiting center

Small intestine

Cell damage

Activation of vagus and splanchnic nerves

Adapted from Grunberg SM et al N Engl J Med 1993;329:17901796.

Release of neuroactive agents

CINV: Emetogenic risk

CINV: Classification

Anticipatory

Acute

Delayed

Chemo

16 - 24 hours

CINV: A Broad Definition

Anticipatory

Early acute Late acute

Delayed

Chemo

16 hours

24 hours

Acute CINV Delayed CINV

No Delayed 76% No Acute CINV Delayed 24%

Yes Acute CINV

No Delayed 20% Delayed 80%

CINV: Current Problem

CINV is still a clinical problem do not fully understand the pathophysiology of CINV (e.g. acute, delayed) traditional definition of acute and delayed CINV does not match the physiology Appears that:
acute CINV impacts delayed CINV prevention of acute CINV may help management of delayed CINV

Acute CINV
Starts within the first 24 hours after chemotherapy administration

Majority of chemotherapeutic agents induce emesis approximately 13 hours following administration

Most researched type of CINV

Remains common despite dramatically improved protection

Pisters KMW, Kris MG. In: Principles and Practice of Supportive Oncology . Lippincott-Raven; 1998. Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer. Ann Oncol 1998;9:811819.

Delayed Chemotherapy-Induced Nausea and Vomiting (CINV)

Starts 24 hours or more after chemotherapy administration First defined with high doses of cisplatin but known to occur with other chemotherapy agents

Carboplatin Cyclophosphamide Doxorubicin Epirubicin Anthracyclines

Mechanism not known; appears to differ from acute emesis

Berger AM et al. In: Cancer: Principles and Practice of Oncology. 6th ed. Lippincott Williams & Wilkins, 2001:28692880. Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer. Ann Oncol 1998;9:811819.

Cisplatin Biphasic Pattern of CINV

Acute Delayed

Time (Days)

Maximal emetic intensity seen within 24 hours postdose Distinct second phase seen, occurring on Days 2 5 postdose

Adapted from Tavorath R, Hesketh PJ Drugs 1996;52:639648. 1996. Used with permission from Adis International Limited.

Postcisplatin: Differential Involvement of Neurotransmitters Over Time

ACUTE (Day 1) DELAYED (Days 25)

Serotonindependent mechanisms (peripheral)

Substance Pdependent mechanisms (central)

12

24

120

Hours after cisplatin

Hesketh PJ et al Eur J Cancer 2003;39:10741080.

Serotonin and 5-HT3 Receptor Pathway

First recognized with high-dose metoclopramide Development of 5-HT antagonists has had dramatic 3 impact

Highly effective in acute vomiting, less effective for delayed events Optimal use is with dexamethasone

Primary mechanism of action appears to be peripheral

Berger AM et al. In: Cancer: Principles and Practice of Oncology. 6th ed. Lippincott Williams & Wilkins; 2001:28692880. Gralla RJ et al J Clin Oncol 1999;17:29712994. Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer. Ann Oncol 1998;9:811819. Endo T et al Toxicology 2000;153:189201. Hesketh PJ et al Eur J Cancer 2003;39:10741080.

5HT3 Receptor Antagonists

Prototypes:
Ondansetron Granisetron Dolasetron Palonosetron

MOA: Inhibition of 5-HT3 receptors on vagal afferent neurons in GI and in CTZ Efficacy improved when used with a steroid Well tolerated, minimal side effects
headache constipation bradycardia

Half-Life and Binding Affinities of 5-HT3 Receptor Antagonists

5-HT3 Antagonist Half-Life (h) Binding Affinity (pKi)* 10.45

Palonosetron (Aloxi) Ondansetron (Zofran) Dolasetron (Anzemet) Granisetron (Kytril)

*Log-scale.
In

40.0 4.0 7.3 9.0

8.39 7.60 8.91

vitro data; clinical significance has not been established.

Substance P
prototypic neuropeptide of the 50 known neuroactive molecules
now recognized as a member of the tachykinin family of neurotransmitters neurokinins are tachykinins found in mammals (substance P, NKA, NKB) 3 categories of NK receptors NK1 - affinity for substance P NK2 - affinity for NKA NK3 - affinity for NKB

currently considered a modulator of nociception, stress, anxiety, nausea / vomiting

DeVane CL. Pharmacotherapy 2001:21:1061-9

CINV
CTZ Neurokinins: Substance P vestibular

GI

Cortical

Emetic Center

Nausea / Vomiting

CINV: Aprepitant
aprepitant (Emend, Merck & Co., Inc.) approved in the US in 2003 Mechanism of action:
selective, high affinity antagonist of human substance P at neurokinin 1 (NK1) receptors interferes with the substance P pathway that produces N/V no affinity for serotonin (5HT3), dopamine and corticosteroid receptors

Indication:
combination with other antiemetics indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy

Aprepitant Administration
Given for three days as part of a regimen that includes a 5-HT3 antagonist and a corticosteroid

Recommended dose
125 mg po 1 hour prior to chemotherapy 80 mg daily in the morning on days 2 and 3

Supplied in 125- and 80-mg capsules

Aprepitant: Challenges for Care

Potential drug interactions with anticancer medication Evaluation of drug interactions should look at impact beyond 24 hours Potential drug interactions with other medications (e.g. chronic)

CINV
CTZ Neurokinins: Substance P vestibular

GI

Cortical DA

5HT

Emetic Center

Nausea / Vomiting

CINV: Triple Upfront Therapy Rationale: Clinical Guidelines

Guidelines include triple upfront therapy for highly emetogenic regimens:
MASCC NCCN 2007 ASCO 2006 Kris MG, et al. JCO 2006:24:2932

Nausea:
Antiemetics Diet (avoid fried, fatty foods) Smaller meals

Diarrhea: Causes
Chemotherapy Infection Malabsorption Radiation induced Clostridium diffecile infection

Diarrhea

Chemotherapy induced

Irinotecan 5-FU (50-80%)

Supportive management

Fluids & Electrolytes Nutrition Avoid problem foods and drugs

Medication management

Opioids
Loperamide (more effective) Diphenoxylate

Nephrotoxicity

Chemotherapy induced nephrotoxicity

Alkylating agents
Cisplatin Ifosfamide Carmustine Carboplatin

Antimetabolites
Methotrexate Gemcitabine

Other
Mitomycin C

Prevention of Nephrotoxicity

Cisplatin

Metrotrexate

Fractionate dose Continuous IV Adequate hydration Use mannitol (increase urine volume) Prevent dehydration Amifostine Carboplatin substitute (not for all case esp in germ cell tumor

Adequate hydration Alkalinize of urine Leucovorin rescue

Ifosfamide

Fractionated doses Hydration Monitor fluid retention (body weight)

Bladder Toxicity: Hemorrhegic Cystitis

Agents

Ifosfamide, cyclophosphamide high dose acrolein accumulation in bladder

Clinical presentation

Onset : 2-3 days Hematuria, dysuria

Prevention
Treatment

MESNA + adequate prehydration

Stop chemo Hydration Adequate platelet

CNS Toxicity

Agents

MTX (IT or IV) Cytarabine Ifosfamide L-asparaginase Cisplatin Lhermitts phenomena 5-FU Taxanes IFN alpha Vinca alkaloid (wrong route NEVER IT)

Neurotoxicity
High dose cytarabine ataxia L-asparaginase drowsiness, stupor Cisplatin ototoxic, ataxia Etoposide Vinca alkaloid jaw pain,cranial nerve pulsies Procarbazine Metrotrexate acute arachnoiditis Oxaliplatin sensory neurotoxic (cold trigger symptom parathesia

Prevention/Treatment chemotherapy induced neuropathy

Peripheral Neuropathy
Sense of touch is distorted- ordinary touch can be unpleasant or painful. Burning or prickling feeling without stimulus Decreased touch sensation Difficulty sensing the position, location, orientation, and movement of the body and its parts (Proprioception) Important to report ANY of these symptoms to health care provider

Colon Cancer Treatment-Progress and Progress, Summer 2005, Vol.1

Cardiotoxicity

Agents

Anthracyclines Cyclophosphamide 5-FU Trastuzumab (Herceptin) Bevacizumab Cisplatinin (Platinol)

Anthracyclin induce cardiotoxicity

Congestive heart failure (mortality >20%) Risk factors

Cumulative dose (> 450 mg/m2 in Thai) Dosing schedule Age (>65 or <4) HTX mediastinal irradiation Preexisting heart disease and arterial hypertension Diabetes Gender (female)

Anthracyclines cardiotoxicity: prevention and treatement

Avoiding anthracyclines Lowering cumulative dose Lowering peak dose nd generation anthracyclines (Idarubicin, epirubicin, 2 mitoxantrone) Early detection of subclinical cardiotoxicity (Echocardiography) Oxygen free radical scavengers vit.E, C, CoQ10 Liposomal formulations

Pulmonary Toxicity

Risk factor

Cumulative dose: bleomycin busulfan carmustine, aldesleukin Age: bleomycin Radiotherapy: bleomycin busulfan, mitomycin, cyclophosphamide, doxorubicin, actinomycin Oxygen therapy: bleomycin, cyclophosphamide, mitomycin

Prevention

Avoid risk factors Amifostine Free radical scavenger Early detection

Treatment

Corticosteroids Diuretics (edema)

Hand-Foot Syndrome

Description

Local cutaneous reaction after chemo. Seen on palms, finger, soles 2-12 days after chemo Tingling, burning of palms, hand, feet Pain, peeling Resolution in 7-14 days after stopping medication

Hand-Foot syndrome
Common in high dose therapy, prolonged infusion, liposomal forms Agents

Management

Capecitabine Cytarabine Docetaxel Daunorubicin Doxorubicin 5-FU (infusion) MTX

Stop dosing Topical wound care & cold cream base Pain management Steroid creams Pyridoxine Avoid heat and pressure

Hematologic complications
Febrile neutropenia Anemia Thrombocytopenia

Hematologic Toxicity: Prophylaxis Recommendations (NCCN 2008 guidelines)

Prevention & Treatment

Febrile neutropenia

Monitor fever (>38.5 C) ANC < 1.0 x 109 /L

Anemia Thrombocytopenia

Hb < 10 g/dL

Antibiotics/antifungal/anti viral prophylaxis (CSF prophylaxis) Blood transfusion (Epoitin alpha)

Platelet < 20,000 / mm3

Platelet transfusion

Stomatitis and Mucositis

Occurs later in cycle with capecitabine Baking Soda and salt mouthwash Over the counter (OTC) enzyme containing mouthwash for dry mouth OTC dental anesthetic Stomatitis cocktail: 1:1:1 antacid solution containing aluminum hydroxide, magnesium hydroxide/viscous lidocaine/diphenhydramine

National Peer Reviews in Colorectal Cancer, Scientific Updates from the 30th annual ONS Meeting, Orlando, Fl. 2005

Stomatitis
Soft toothbrush Mild toothpaste Mild gargles Ice cubes Ibuprofen

Pain

Cancer pain is common but not inevitable

Fatigue, GI upset, and psychosocial problems are often more prevalent, but pain is the #1 feared aspect of cancer for most patients

Rates of pain vary widely among disease sites:

35% in lymphoma 56% in breast cancer 67% in head and neck cancer

Monitoring Outcome: The 4 As

Analgesia (pain relief) Activities of Daily Living (psychosocial functioning) Adverse effects (side effects)

Aberrant drug taking (addiction-related outcomes)

(Passik and Weinreb, 1998)

Communicating About Pain

Communicate

Intensity Location What the pain feels like What makes it worse What helps

Pain Intensity Rating

Numerical Rating Scale

Category Scale

Wong-Baker FACES Pain Rating Scales

WHO Analgesic Ladders

Analgesic Classification
1.Opioids 1. weak/full agonist, partial agonist and mixed agonistantagonist (ceiling effect) 2. strong/full agonist (no ceiling effect no maximum dose) 2.NSAIDs (ceiling effect) good for bone pain 3.Adjuvant analgesic or coanalgesics 1.TCA (amitryptyline) for neuropathic pain 2.Antiepileptics (gabapentin, oxcarbazepine) for neuropathic pain 3.Steroids for cord compression 4.Bisphosphonates

Concern about analgesics

Opioids

Some Should not for chronic use

Meperidine (neurotoxic) Dextropropoxyphene (toxic) Buprenorphine (partial agonist) Nalbuphine (mix ago/antagonist)

Constipation sennosides, bisacodyl, MgOH N/V ondansetron Respiratory depression (Naloxone) Sedation caffeine to resolve

What Not to Fear

Addiction Tolerance (using meds too soon, i.e., before I really need them) Side effects

Good treatments exist for nausea, sedation and a ground breaking treatment will soon be available for constipation

Pain Treatment

Acute Pain (Somatic and visceral pain)

Morphine bolus or IM morphine When pain is relieved, off morphine oral weak opioids or NSAIDS

Chronic pain

Around the clock medication opioids (long acting)

Neuropathic pain

Amitriptyline (10-75 mg/d) or Pregabalin (150-600 mg/d)

Maintaining Weight and Muscle Mass

Cachexia and Nutritional Risk

Nutritional risk (ie, unwanted weight loss), including cachexia, is a common and distressing problem in advanced cancer, affecting up to 80% of patients (Bruera, 1993)

Negatively affects survival as well as quality of life (Delmore, 1993) Etiologies:

abnormal gastrointestinal functioning anorexia from nausea, anxiety, depression and cognitive dysfunction metabolic abnormalities caused principally by cytokines
(Keller, 1993)

Cachexia and Nutritional Risk

4 main clinical manifestations of cachexia:

Anorexia Chronic nausea Asthenia Change in body image

Pharmacologic treatment of cachexia is targeted principally at anorexia and chronic nausea (Bruera, 1993)

Pharmacological Approaches

The main pharmacologic approaches include:

Corticosteroids Progestational agents (ie, megestrol acetate) Cannabinoids (ie, dronabinol) Antihistamines (ie, cyproheptadine) Unique agents (ie, hydrazine sulfate) Omega-3 fatty acids, EPA and docosahexaneoic acid (DHA) (n-3s) (Barber, et al, 2000; Hussey & Tisdale, 1999; Wigmore, et al, 2000)

Fatigue and Chemobrain

Fatigue
Highly prevalent effecting 2/3s of patients Very disabling Also makes the job of caregiving more stressful and exhausting for family

Fatigue what works?

Exercise Modifications in diet Stimulant medications

Acneform Rash
Avoid sun, heat & humidity Use mild soaps Water based makeup is generally well tolerated Pharmacologic Mgmt. Topical and/or antibiotics Topical and/or oral antihistamines Cool compresses Petroleum jelly, silver sulfadiazine ointment for ulcerative lesions

Multiple white bands in the nails, representing periods of growth arrest, in this case due to cycles of treatment with 5-fluorouracil.

Oncologic Emergency

Oncologic Emergencies

Sepsis and disseminated intravascular coagulation

Collaborative management includes:

Prevention (the best measure) Intravenous antibiotic therapy Anticoagulants, cryoprecipitated clotting factors

Spinal Cord Compression

Tumor directly enters the spinal cord or the vertebrae collapse from tumor degradation of the bone.
(Continued)

Spinal Cord Compression (Continued)

Collaborative management includes:

Early recognition and treatment Palliative High-dose corticosteroids High-dose radiation Surgery External back or neck braces to reduce pressure in the spinal cord

Hypercalcemia
Occurs most often in clients with bone metastasis Fatigue, loss of appetite, nausea and vomiting, constipation, polyuria, severe muscle weakness, loss of deep tendon reflexes, paralytic ileus, dehydration, electrocardiographic changes

(Continued)

Hypercalcemia (Continued)

Collaborative management includes:

Oral hydration Drug therapy Dialysis

Superior Vena Cava Syndrome

Superior vena cava is compressed or obstructed by tumor growth. Condition can lead to a painful, life-threatening emergency. Signs include edema of face, Stokes sign, edema of arms and hands, dyspnea, erythema, and epistaxis.

(Continued)

Figure 1 Photographs of the patient showing the reduction in swelling of the face, neck and upper extremities

Chee CE et al. (2007) Superior vena cava syndrome: an increasingly frequent complication of cardiac procedures Nat Clin Pract Cardiovasc Med 4: 226230 doi:10.1038/ncpcardio0850

Superior Vena Cava Syndrome

(Continued)

Late-stage signs include hemorrhage, cyanosis, change in mental status, decreased cardiac output, and hypotension.

Collaborative management includes high-dose radiation therapy, but surgery only rarely.

Tumor Lysis Syndrome

Large numbers of tumor cells are destroyed rapidly, resulting in intracellular contents being released into the bloodstream faster than the body can eliminate them. Collaborative management includes:

Prevention Hydration Drug therapy (Allopurinol)

Conclusions
People with cancer are living longer The focus is on quality of life in addition to quantity People surviving cancer want to live normal lives People with cancer have multiple symptoms New treatments of various kinds are available and there is no need to suffer