Oncology Pharmacotherapy

Objectives
Describe etiology & diagnosis of cancer
Define cancer staging system
Describe relative roles of available treatments
Chemotherapy, radiation, surgery
Classify chemotherapeutic drugs and distinguish
mechanisms and adverse effects
Identify common medications (& their rational) for
common malignancies, including supportive care
 Etiology
Uncontrolled cell growth with tissue invasion and
spread (metastases) to other parts of the body
Cells Called
Epithelial Cells Carcinoma
Muscle, connective tissue Sarcoma
Glands Adenocarcinoma
Bone marrow, lymphoid Leukemia, lymphomas

Common types:
Males Females
Prostate Breast
Lung, Colon, Lymphoma
 Etiology 2
Carcinogenisis
Exposure to toxins:
smoking & sun; hormones & medications
Genetics:
Oncogenes (Turn on => cancer)
Tumor-Suppressor Genes (Turn off => cancer)
Examples Cancer type
Oncogenes
Epidermal Growth Factor Receptors Breast Cancer
EGFR, ERB-B1, HER 2
Tumor-Suppressor Genes
BRCA Breast Cancer
Tumor Growth
 Screening & Detection
Adults
Change in bowel or bladder
habits
A sore that does not heal
Unusual Bleeding or discharge
Thickening or lump in breast
or elsewhere
Indigestion or difficulty in
swallowing
Nagging cough or hoarseness
Screening (age, family history)
Colonoscopy
Mammography
Children
Continued, unexplained weight loss
Headaches with vomiting in the morning
Increased swelling or persistent pain in
bones or joints
Lump or mass in abdomen, neck or
elsewhere
Development of whitish appearance in the
pupil of the eye
Recurrent fevers not caused by infections
Excessive bruising or bleeding
Noticeable paleness or prolonged tiredness
 Diagnosis & Staging
Diagnosis Staging (TMN)
MUST get tissue for 0, 1; IIA, IIB; III A, III B, III C; IV
pathologic diagnosis Tumor (T)
Cytogenetics, Tumor markers Tx, T0, Tis
Lab T1-T4
Complete blood cell count, Regional lymph nodes (N)
electrolytes, renal & liver
function Nx, N0
N1-N2
Radiology
X-rays, CT scans, MRI et al
Distant Metastasis (M)
Mx, M0
M1
 Treatment
Modalities
Surgery
diagnosis and reduce / remove
Radiation
Treatment / cure, also palliative
Pharmacotherapy
Chemotherapy, Hormones, Immunotherapy
Targeted biologic agents
Goals
Cure, Complete Response, Partial Response, Stable
Disease, Palliative.
 Pharmacotherapy
Chemotherapy Examples
Antimetabolites Flurouracil, Capecitabine; Cytarabine, Gemcitabine
6-mercaptopurine; Methotrexate
Alkylating Cyclofosphomide, Ifosfamide;
& Dacarbazine, Temoxolomide; Busulfan
Heavy-Metals Cisplatin, Carboplatin, Oxaliplatin
Topoisomerase Etoposide, Irinotecan

Anthracycline Antibiotics Doxorubicin, Daunorubicin

Tubulin active Vincristine, Vinblastine;
Pacitaxel & Docetaxel
Miscellaneous Bleomycin; L-Asparginase;
Hydroxyurea, Tretinoin, Thalidomide
Hormonal Bicalutamide, Flutamide; Anastrozole, Tamoxifen
Immune Therapy Interferon, Aldesleukin
Targeted Biological Examples
Monoclonal Antibodies Mabs: Rituximab
Tyrosine-Kinase Inhibitors Nibs: Imatinib
 Chemotherapy
Chemotherapy Examples

Antimetabolites Flurouracil, Capecitabine; Cytarabine, Gemcitabine

6-mercaptopurine; Methotrexate
Alkylating Cyclofosphomide, Ifosfamide;
& Dacarbazine, Temoxolomide; Busulfan
Heavy-Metals Cisplatin, Carboplatin, Oxaliplatin
Topoisomerase Etoposide, Irinotecan

Anthracycline Antibiotics Doxorubicin, Daunorubicin

Tubulin active Vincristine, Vinblastine;

Pacitaxel & Docetaxel
Miscellaneous Bleomycin; L-Asparginase;
Hydroxyurea, Tretinoin, Thalidomide
 Chemotherapy

Mechanisms of Action Antimetabolites

Alkylating
& Heavy Metals
Topoisomerase

Anthracyclines

Tubulin active

Miscellaneous
Cell Cycle Specificity
 Cell Cycle Specificity
Specific:
Works on reproducing (non-resting) cells
There will always be some cells still alive
Schedule dependent
Usually (but not always) as infusion
Non-Specific:
Works on all cells
Dose Dependent
Bolus (probably better but not always) or infusion
 Toxicity
Targets rapidly dividing cells:
Narrow therapeutic range and distinctive toxicity
Bone marrow / myelosuppression (WBC, RBC, Plts)
Mucus membrane & skin
esophagitis, diarrhea & alopecia
Nausea & vomiting via CRZ
Other adverse effects
Pro-malignant
Extravasation (tissue damage if gets outside vein)
Hypersensitivities
Organ Drug specific (lungs, heart)
 Selected NCI Toxicity Criteria
Toxicity Grade 1 Grade 2 Grade 3 Grade 4
Mild Moderate Severe Life-threatening
Neutropenia > = 1,500 1,500 1,000 < 1,000 500 < 500
(per mm3)
Thrombocytopenia > = 75,000 < 75,000 50,000 < 50,000- 25,000 < 25,000
(per mm3)

Nausea Loss of Oral intake Inadequate oral Life-threatening

queasy sensation appetite decreased caloric or fluid consequences;
and/or the urge without Without significant Intake; tube urgent intervention
to vomit. alteration in weight loss, feeding, TPN, indicated
eating habits dehydration or hospitalization
or malnutrition indicated
Vomiting 1 - 2 episodes 3 - 5 episodes >=6 episodes Life-threatening
reflexive act of (separated by (separated by (separated by consequences;
Ejecting contents 5 minutes) 5 minutes) 5 minutes) in 24 hrs; urgent intervention
of in 24 hrs in 24 hrs tube feeding, TPN indicated
stomach through or hospitalization
mouth. indicated
 Antimetabolites
False or faulty substrates that inhibit form,
function or maintenance of DNA
Cell-cycle specific
Antimetabolites Substrate
Flurouracil, Capecitabine; Pyrimidine

Cytarabime, Gemcitabine Cytosine

6-mercaptopurine Purine

Methotrexate Folate
 Antimetabolites - Pyrimidine
5-fluorouracil (5-FU)
Prodrug; Hepatic Elimination
Activity increased by folinic acid
Colorectal, breast, other GI & Head and Neck CA
Side effects:
Bolus: Stomatitis, Esophagitis; neutropenia
Infusion: Diarrhea
Uncommon: Neuro, Cardiotoxicity.
Capecitabine
Oral prodrug of 5-FU
Like 5-FU, more myelosuppression & palmar-plantar
erythrodyesthesia; Affects INR
 Antimetabolites - Cytosine
Cytarabine
Renal elimination
IV as low dose continuous, high-dose intermittent
Hematological malignancies only
Myelosuppression, Cerebellar syndrome
Gemcitabine
Non-renal elimination
Non Squamous Cell Lung, Bladder & GI cancers
Myelosuppression, flu-like symptoms, rash
 Antimetabolites - Purine
6 mercaptopurine
Catabolized by thiopurine S-methyltransferase
(TPMT) w/ genetic polymorphisms
Increases risk of myelosuppression
Allopurinol interaction
Acute lymphocytic and chronic myelogenous
leukemia
Myelosuppression, mild nausea, skin rash
 Antimetabolites - Folate
Methotrexate
Inhibits dihydrofolate reductase
Renal elimination & nephrotoxic
Rx: Adjust dose, vigorous hydration & alkyation of urine
Lymphoma, gastric, esophageal, bladder, ALL
Myelosuppresion, N/V, mucositis; drug interactions
Activity blocked by folinic acid
used to rescue cells after high doses of MTX
Started at 24 hours & titrated to MTX levels
 Alkylating & Heavy-Metals
Oldest group
Alkylating: add group to DNA, inhibit replication
Heavy Metals: reactive platinum complex binds cell

Chemotherapy Examples

Alkylating Cyclofosphomide, Ifosfamide;

& Dacarbazine, Temoxolomide; Busulfan
Heavy-Metals Cisplatin, Carboplatin, Oxaliplatin
 Alkylating Agents
Cyclophosphamide
Activation produces nephrotoxic substance (acrolein)
Hemorrhagic cystitis
Prevent with vigorous hydration +/- dose-dependent MESNA
Wide range of activity; given PO or IV
Delayed (12h) N/V, myelosuppression, alopecia et al
Ifosphamide
More CNS toxic & cystitis: ALWAYS give MESNA
ALL, Lymphoma, breast, ovarian, lung
 Heavy Metals (Platinum)
Efficacy Safety
Cisplatin Wide range V. High N/V
IV, Renal Nephrotoxic
Carboplatin Ovary, lung, breast Moderate N/V
IV, Renal Testicular, esophageal More myelosuppression,
head & neck Thrombocytopenia,
otherwise less toxic vs Cisplatin
Hypersensitivity
Oxaliplatin Colorectal CA Moderate N/V
IV Neuropathy (Cold-induced et al)
 Topoisomerases
Epidophyllotoxin derivatives
Cell-cycle specific
give divided doses over several days
IV over 30-60 minutes
Myelosuppresion
Etoposide
Teniposide
 Topoisomerases
Anthracyclines
Doxorubicin (Adriamycin) et al
Inhibit Topo II and generate free radicals
Antitumor antibiotics
Extravasations
Cardiotoxic:
Total cumulative dose
Method or schedule of administration
Concurrent therapy
Pre existing heart disease
Previous use of other anthracyclines
 Anthracycline Cardiotoxicity
Drug Maximum lifetime
Doxorubicin 400-450mg/m2
Daunorubicin 450-550mg/m2
Epirubicin 900-1000mg/m2
Idarubicin 150mg/m2
Mitoxantrone much lower risk
Also less damage with extravasations

Drug given by bolus injection with

no underlying co morbidities (heart, kidney disease)
 Tubulin Active
Inhibit mitosis
Cell cycle specific for M phase
Vinca Alkaloids (periwinkle)
Vincristine, Vinblastine
Taxanes (yew trees)
Paclitaxel, Docetaxel
 Vinca Alkaloids
Vincristine, Vinblastine
Hepatic elimination
Neurotoxicity
Peripheral (hands & feet)
Automomic (GI give laxitives)
Fatal if given intrathecal
Paclitaxel & Docetaxel: myelosuppression
Paclitaxel: hypersensitivity (premedicate) & neurotoxicity
Docetaxel: Fluid retention due to capillary leak
(premedicate with dexamethasone)
 Miscellaneous
Bleomycin
Antitumor antibiotic mix from streptomyces
Acts at DNA with free radicals; Cell cycle specific
Inactivated in cells by aminohydrolase
Low levels of enzyme in lungs or skin = high drug levels
Not myelosuppressive!
Pulmonary toxicity with lifetime max dose < 300 IU
Hypersensitivity & skin (palms of hands) reactions
 Miscellaneous
L-Asparginase
Unique mechanism
Works for ALL & childhood AML
Severe allergic reactions
Tretinoin & Thalidomide
Tretinoin: retinoic acid syndrome (like pneumonia)
Thalidomide: used for Multiple Myeloma
Chemically unrelated, both severe teratogens
 Other key principles
Combination therapy
Avoid overlapping mechanisms & toxicity
Resistance mechanisms
Decreased activation of prodrugs
P-glycoprotein efflux pumps
Order of administration matters!
Giving cisplatin first delays clearance of subsequent
Methotreaxte, Paclitaxel
Mechanism of action helps you understand side
effects & predict and manage them
 Hormonal
Prostate cancer
Antiandrogens:
Bicalutamide, Flutamide
Luteinizing Hormone Releasing Hormone (LHRH)
Agonists
Decreases Testosterone & estrogen levels via negative
feedbact
Goserelin & Leuprolide
 Hormonal
Breast Cancer
Aromatase inhibitors: lower estrogen levels
Anastrozole, Letrozole
Estrogen receptor antagonist
Tamoxifen
Fulvestrant
Corticosteroids
Lymphotoxic
 Immunotherapies
Interferons
Enhance immune systems attack
Melanoma, kidney, Kaposis sarcoma, CML, Lymphocytic
Leukemia
Poorly tolerated: flu like symptoms, depression.
Interleukin 2 (Aldesleukin)
Promotes B & T cell proliferation
Kidney, Melanoma
Hypotension / shock, rigors & chills
 Targeted Biological Therapies
Why: selective toxicity by targeting proteins
unique to cancer cells
Monoclonal Antibodies
Small Molecule drugs
Apoptosis-inducing drugs
Angiogenesis inhibitors
Cancer vaccines
 Targeted Biological Therapies
Monoclonal Antibodies (-mab), usually IgG
May be conjugated to increase response
Immunotoxin, chemo or radioactive particle
25 % of new cancer drugs are mabs
50% of mabs indication are for cancer
Binds antigen target unique to the cancer cell &
trigger immune response (killing)
May carry radiation = hot
 Immunogenicity & Naming of Mabs
Allergic type reactions (antihistamines, steroids)
and decreased response over time
Human anti-mouse antibodies (HAMA)
Least reactions with human source
Syllable Source
U Human
O Mouse
A Rat
E Hamster
I Primate
Xi Cross (human/animal)
Chimeric mix
 Examples of Mabs
Yr Name Antibody Antibody Structure Target Approved
Source Indication
1997 rituximab Chimeric unconjucated CD20 Low grade
NHL
1998 Trastuzumab Humanised unconjucated HER MBC-HER
2+++
2000 Gemtuzumab Humanised toxin conjugated CD33 AML
ozogamicin
2001 Alemtuzumab Humanised unconjucated CD52 CLL
2002 yttrium -90 Murine radiolabeled CD20 Low grade
-ibritumomab NHL
2003 iodine -13 Murine radiolabeled CD20 Low grade
1-tositumomab NHL
2004 bevacizumab Humanised unconjucated VEGF MCR
2004 Cetuximab Chimeric unconjucated EGFR1 MCR
 Rituximab

Mouse
CD20+ cell
Human

Chimaeric anti-CD20 monoclonal antibody

Direct anti-tumour effects
Sensitises chemo resistant cell lines
CD20 + B-Cell lymphoma, Non Hodgkins Lymphoma
 Interaction of Rituximab
With Host Immune Effector Cells

CD20

Killer Complement
leukocyte Malignant
B cell
CD20

Rituximab Rituximab

Antibody-Dependent Cellular Complement-Dependent

Cytotoxicity (ADCC) Cytotoxicity (CDC)
Adapted from Male et al. Advanced Immunology. 1996;1:1.
 Event-free Survival among 399 Patients Assigned to
Chemotherapy with CHOP or with CHOP plus Rituximab

N Engl J Med 346:235

 Trastuzumab
Epidermal Growth Factor Receptors (EGFR): HER -2
HER-2 over expressed in 30 % of Breast CA
aggressive disease, high risk of relapse, poor survival

Trastuzumab
Recombinant humanized mab targeting HER-2
4 different mechanisms including ADCC
Standard of care for HER-2 + breast CA
Distinctive toxicities
Cardiac (7% of patients) so check LVF (echocardiogram)
Pulmonary
 Bevacizumab
Vascular Endothelial Growth Factor (VEGF)
VEGF needed to stimulate growth of new blood
vessels (angiogenesis) to feed tumor
Bevacizumab
Humanized mab binds VEFG, prevents activity
Colorectal, kidney, lung, breast, head, neck
Causes hypertension (sustained, needs treatment)
Rare/severe: Bleed, delayed wound healing,
kidney damage et al
 Cetuximab
Chimeric (mixed) mab that binds EGFR
EGFR in 80% colorectal CA
Doesnt work on some (KRAS +) colorectal CA
Colorectal, head & neck CA
20% of patients get
Asthenia/malaise
Abdominal pain
Fever
Infusion reaction
Acne like rash after 1-3 weeks
Severity correlates with efficacy!
 Alemtuzumab
Targets CD52 receptor on B & T
lymphocytes
Treats CLL
Immuno-suppression
Severe & prolonged (6 months)
Prophylaxis against infection using cotrimoxazole &
antivirals
 Radiotherapy
Hot antibody targeting CD20 (like rituximab)
Hematological toxicity is delayed, prolonged and
profound
131 I tositumomab w/ radioactive idoine
Must add thyroid blocking agents
Yttrium-90 (90Y) ibitumomab tiuxetan
 Tyrosine Kinese Inhibitors (TKI)
Small molecule inhibitors of transmembrane
protein receptors
Low molecular weight = given PO
 Small Molecule Drugs & Targets
Drug name Target FDA Approved use
Imatinib (Gleevec) BCR/ABL for CML and c-kit for GIST CML/ GIST
Gefitinib (Iressa ) EGFR Advanced NSCLC
Erlotinib (Tarceva) EGFR Advanced NSCLC
Dasatinib (Sprycel) BCR-ABL, SRC CML
Temsirolimus (Torisel) mTOR Renal Cell CA
Lapatinib (Tykerb) Inhibition of EGFR and HER2 Advanced Breast ca
Example: Imatinib (Gleevec)
 Imatinib
Oral TKI specific for BCR-ABL (Philadelphia
chromosome) fusion gene in CML
Mild to moderate reactions
Severe fluid retention, less than 10 % of patients
Rash which may progress to Stevens-Johnson
Syndrome
Metabolized by and inhibitor of CYP3A4
Oncology Supportive Care
 Common Severe Toxicities
Bone marrow / myelosuppression
Neutropenia (WBC)
Anemia (RBC)
Platelets (Plts)
Mucus membrane & skin
Esophagitis, diarrhea
Extravasation & alopecia
Nausea & Vomiting via CRZ
 Bone Marrow Toxicity
Pattern and cell lines vary by drug and dosing
Neutrophils & Platelets follow each other
Nadir: lowest level
Onset, duration and severity
Need recovery before giving more chemo
Gets worse with each cycle
Some chemo is not toxic to bone marrow:
Vincristine, asparaginase and bleomycin
 Half Life & Growth Factors
Neurophils 6-8 hrs
GM-CSF Sargramostim
G-CSF Filgrastim
Thrombocytes, 5-7 days
Thrombopoietin Oprelvekin
Erythrocytes, 120 days
Erythropoietin Epoetin
 Bone Marrow Toxicity
Drug/ Drug Class Severity Nadir (days) Recovery (days)
Nitrosoureas High 25-60 35-80
Busulphan High 11-30 24-54
Carboplatin High 16 21-25
Anthracyclines High 6-13 21-24
Methotrexate High 7-14 14-21
Mercaptopurine High 7-14 14-21
Fluorouracil Low-High 7-14 22-24
Epidophylotoxins Mod 5-15 22-28
Melphalan Mod 10-21 18-40
Chlorambucil Mod 10-21 18-40
Procarbazine Mod 25-36 35-50
Mitomycin C Mod 28-42 42-56
Cisplatin Low Mod 14 21
Vinca Alkaloids Low -Mod 4-9 7-14
 Neutropenia
Profound increase in risk of infection especially at
ANC < 500 (see ID talks for Febrile Neutropenia)
G-CSF (Filgrastim), GM-CSF (Sargramostim)
reduces incidence, magnitude & duration
Primary Prophylaxis
Regimens / patients with > 20% risk of febrile neutropenia
Established Neutropenia - Not clear; give if high risk
Neutropenia > 10 days, ANC < 100 cells / mm3, Age > 65 y,
infectious complications, or hospitalized at onset of fever
 Anemia
Common and affects quality of life
Assess other causes (bleeding, folate, iron)
Target is 11 -12 mg/dL (NOT higher)
Transfusions if acute / bleeding
Erythropoetin (Epoetin), Darbopoetin (long acting)
Start at < 11 mg /dL
Goal of increase of 1 mg/dL, decline in ferritin or
increase in reticulocyte count after 2-4 weeks
Start at 40,000 units Epoetin each week
 Thrombocytopenia
Risk of bleeding
Transfuse platelets at < 10,000 cells / mm3
At higher if bleeding, surgery needed or infection
Secondary prophylaxis if patient history of
significant thrombocytopenia with past chemo
Oprelvekin decreases need for transfusions
Fluid retention (edema et al)
Cardiotoxicity
Expensive
 Mucous Membranes
Mucositis within 5-7 days
5-FU, doxorubicin & methotrexate
Supportive care, nutrition, & avoid infection
Good oral hygiene, dentist evaluation
Ice chips during 5-FU treatment
Topical analgesics & antihistamines (Magic Mouthwash)
Viscous lidocaine, diphenhydramine & dyclonine (or nystatin)

Diarrhea
If no infection: Lomotil or loperamide
Severe cases: Octreotide
 Skin
Extravasations
Anthracyclines; vinca alkaloids, taxanes et al
Prevention, deep central line for administration
Ice packs (heat for vincas)
Drug specific antidotes
Sodium thiosulfate for nitrogen mustard
Cutaneous Reactions
EGFR active agents; Cytarabine, 5-FU, Bleomycin
 Skin et al
Alopecia
Supportive care, wigs
Infertility
Secondary Malignancies
Tumor Lysis Syndrome
Hyperuricemia: release of intracellular content
High tumor burden (ALL, lymphoma)
Allopurinol 300-600mg for 5-7 days
Hyperhydration
Urine alkalisation
 Chemotherapy Induced
Nausea and Vomiting (CINV)
Nausea, Retching, Vomiting
3 main causes:
Stimulation of chemotherapy receptor zone (CTZ)
in 4th ventricle
Stimulation of GI tract
Sensory input and memory
3 main types
Acute = within 24 hours
Delayed = after 24 hours
Anticipatory = before chemo given
 Pathophysiology of
Chemotherapy-induced nausea
 Patient Risk Factors
Risk Factor Risk
Age Children > Adults
Gender Women > Men
History Increased if h/o
Motion Sickness
Prior N/V with Chemo, Radiation
Heavy Alcohol Use Protective against N/V
 Drug Classes for CINV
Stimulation of chemotherapy receptor zone (CTZ)
NK 1 Inhibitors (Aprepitant)
Cannabanoids (Dronabinol)
Phenothiazines (Promethazine)
Dopamine antagonists
Metoclopramide; Haloperidol
Antihistamineanticholinergics (Diphenhydramine)
 Drug Classes for CINV
Stimulation of GI tract
Selective Serotonin Reuptake Inhibitors
SSRI = HT3
Ondansetron
Granisetron
Dolasetron
Sensory input and memory
Benzodiazepines (Lorazepam)
Drug treatment of CINV

NK1 Inhibitors
 Emetogenicity
High Risk > 90 % Moderate Risk 90 30 % Low Risk 30 - 10 %
Carmustine Carboplatin Bortezomib
Cisplatin Cytarabine >1 g/m2 Cetuximab
Cyclophosphamide Cyclophosphamide Cytarabine 1 g/m2
1,500 mg/m2 <1,500 mg/m2 Docetaxel
Dacarbazine Daunorubicin Etoposide
Dactinomycin Doxorubicin Fluorouracil
Mechlorethamine Epirubicin Gemcitabine
Streptozotocin Idarubicin Methotrexate
Ifosfamide Mitomycin
Irinotecan Mitoxantrone
Oxaliplatin Paclitaxel
Pemetrexed
Topotecan
Trastuzumab
 Prophylaxis of CINV
Emetic Risk Acute Delayed
High SSRI + Day 2 & 3 post
DEX + DEX +
Aprepitant Aprepitant
Moderate Anthracycline +
cyclophosphamide Day 2 & 3 post
SSRI + DEX + Aprepitant
Aprepitant
Others Day 2 4 post
SSRI + DEX SSRI OR DEX

Low Dexamethasone None

Minimal None None
 Treatment of CINV
Primary goal is prevention!
Chlorpromazine, prochlorperazine, promethazine,
Methylprednisolone, Dexamethasone
Lorazepam (good for amnesic effects)
Metoclopramide,
Dronabinol
Drug IV Dose PO Dose
Ondansetron 8mg or 0.15mg/Kg 16 mg (8 mg BID
Granisetron 1mg or 0.01mg/kg 2 mg (or 1mg)
 Pain
5th vital sign
Subjective, debilitating & difficult to quantitative
Visual analog scales
Acute or Chronic, Nocicpetive vs Neuropathic
Pharmacotherapy (MLTG Volume 8 April 2010)
Dosing: Basal / Bolus
Management of ADEs
Non-Opioids (Acetaminophen; Salicylates, NSAIDS)
Opioids
Adjuvant
Antidepressants, Anticonvulsants, Others, Topicals