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74 Cards in this Set

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Cancer


(Definition)

A group of diseases:


1.) uncontrolled cellular growth


2.) local tissue invasion


3.) distant metastases

Most commonly diagnosed cancer in men?

Prostate

Most commonly diagnosed cancer in women?

Breast

Most common cause of cancer death in women?

Lung

Most common cause of cancer death in men?

Lung

Age group for which cancer is the leading cause of death?

> 85 years of age

Lifetime probability of developing cancer for men and women?

men = 1 in 2


women = 1 in 3

Top 3 causes of cancer death in children and adolescents?

0-14 years: 1.) Brain, 2.) Leukemia, 3.) Soft Tissue


15-19 years: 1.) Leukemia, 2.) Bone/Joints,


3.) Brain

The 2 major influences in the development of cancer in Americans?

1.) Cigarette smoking


2.) Age

Obesity is a risk factor for which 3 cancers?

1.) Colon


2.) Prostate


3.) Ovarian

What lack in diet is associated with higher rates of cancers?

5 or more servings of vegetables daily

4 Processes in Carcinogenesis

1.) Initiation


2.) Promotion


3.) Conversion


4.) Progression

Initiation


(Definition)

irreversible damage to normal cells caused by exposure to carcinogenic substances

Promotion


(Definition)

carcinogens alter the environment to favor growth of the mutated cells


possibly reversible

Conversion


(Definition)

the transformation of a normal cell to a cancerous cell


may take 5-20 years

Progression


(Definition)

further genetic changes leading to increased cell proliferation

Angiogensis


(Definition)

the development of new blood vessels by the tumor in order to grow

Who do we screen for cancer?

Asymptomatic people with risk factors for certain kinds of cancer because...




- of the low cure rate of metastatic cancer if discovered too late


- the expense of screening

Describe the screening schedule for breast cancer.

Clinical Breast Exam:


- starting at age 20


- at least every 3 years, then annually prior to mammograms




Mammogram:


- starting at age 40


- annually

Describe the screening schedule for cervical cancer.

Pap Smear:


- starting at age 21 to 29


- every 3 years




HPV and Pap Tests:


- starting at age 30 to 65

Describe 5 screening schedules that both men and women should follow starting at age 50.

1.) Fecal Occult Blood Test - annually


2.) Flexible Sigmoidoscopy - every 5 years


3.) Double Contrast Barium Enema - every 5 yrs


4.) Colonoscopy - every 10 years


5.) CT Colonography - every 5 years

Goals of Cancer Treatment

1.) Cure


2.) Prolong Life


3.) Palliation

Adjuvant Therapy


(Definition)

systemic therapy that is administered to treat any existing micrometastases remaining after surgical excision of localized disease.

Neoadjuvant Therapy


(Definition)

treatment given prior to the definitive local treatment, usually prior to surgery.

What order of kinetics do cancer treatments follow?

1st order


(cancer drugs kills a constant proportion of tumor cells)

What kind of cells do most cancer treatments target?

Rapidly proliferating cells, whether cancerous or no. (Ex: mucus membranes, hair follicles, bone marrow)

How are cancer treatments dosed?

The Maximum Tolerated Dose (MTD) is the most effective, but requires several cycles with resting periods in between.




The MTD is given up to the Dose Limiting Toxicity (DLT) for any one anticancer drug at which point it's too dangerous to continue.

Gompertzian Growth Curve-Log-Kill Hypothesis

Cancer cells are clinically undetectable til 10^5


- immunotherapy = greatest benefit




10^5 - 10^12 cells = symptomatic, diagnosis possible, bulk reduction of tumor is necessary




10^12 cells = plateau growth phase, 1 kg tumor, incapacitating symptoms, death

Why Combination Chemotherapy?

1.) Maximal cell kill within tolerated toxicity


2.) Broader range of coverage


3.) Prevent development of resistant lines

Metronomic Therapy


(Definition)

For molecularly-targeted drugs only.


Taken continuously until disease progression or unacceptable adverse events occur.

4 Classes of DNA-Damaging Drugs

1.) Alkylating Agents


2.) Antibiotics


3.) Topoisomerase Inhibitors


4.) Anti-Metabolites

Characterization of DNA-Damaging Drugs

Interfere with transcription and reduplication


- Affected cells undergo cell cycle arrest and apoptosis


* Mutagenic, Teratogenic, and Carcinogenic


Affect rapidly proliferating cells

Alkylating Agents


(Mechanism of Action)

Overall: Attach alkyl groups to DNA




* groups on DNA bases prevent DNA synthesis, RNA transcription = fragmentation


* crosslink DNA strands = no DNA separation for reduplication or transcription


* groups induce mispairing leading to mutations

8 Alkylating Agents

1.) Nitrogen Mustards *


2.) Nitrosureas *


3.) Triazenes and Hydrazines


4.) Ethylene Imines and Methylmelamines


5.) Benzoquinone-containing


6.) Alkyl Sulfonates


7.) Illudins


8.) Platinum drugs *

Nitrogen Mustards

1st Gen: Mechlorethamine *, N-0xide


2nd Gen *: Chlorambucil, Melphalan, Bendamustine, Spiromustine


3rd Gen: Uramustine


Steroid-Coupled: Estramustine phosphate, DHEA mustard, Prednimustine


Phosphoramide *: Cyclophosphamide, Ifosfamide

Which nucleotide is most susceptible to alkylation?

Guanine

Phosphoramide Mustards


(Mechanism of Action)

Prodrugs metabolized by CYP450 to phosphoramides and acrolein




Phosphoramides alkylate DNA


Acrolein alkylates proteins (AE: Bladder Toxicity)

Cyclophosphamide


(Cytoxan)

Uses: solid and hematologic tumors, bone marrow transplant (BMT)




AE: hemorrhagic cystitis (bladder toxicity)


(not as much as Ifosfamide, may give Mensa)




DLT: leukopenia = 8-14 days

Ifosfamide


(Ifex)

Uses: sarcomas, testicular cancer, lung cancer




AE: *hemorrhagic cystitis (Mensa mandatory)

Nitrosoureas


(Mechanism of Action)

Carmustine (BiCNU), Lomustine (CeeNU), Streptozocin (Zanosar)




Lipid Soluble, often oral dosing, long nadir

Carmustine


(BiCNU)

Uses: brain tumors, Hodgkin's Dx, mycosis fungoides, cutaneous T-cell lymphoma




*Dosage Forms: Injection (in EtOH), topical, Gliadel wafer (brain implantation)


*Long time to nadir (21-28 days)


*Administer every 6 weeks



Lomustine


(CCNU, CeeNU)

Uses: primary brain tumors




Dosage Forms: oral capsule (10 mg increments)




Long time to nadir (dose every 6 weeks)

Platinum Compounds


(Mechanism of Action)

Crosslink DNA like mustards


- intrastrand (bind twice, same strand)


- interstrand (bind twice, crosslink)


- monoadduct (bind once)


- intermolecular (bind to DNA and protein)

Cisplatin


(Adverse Effects)

Nephrotoxicity


Nausea/Vomiting (acute and delayed)


Neuropathy


Myelosuppression (slight)


Ototoxicity

Carboplatin


(Adverse Effects)

Uses: broad spectrum




AE: nephrotoxicity, ototoxicity, neuropathy, N/V


(less than cisplatin)


myelosuppression




DLT: Thrombocytopenia

Carboplatin


(Dosing)

Calvert Formula


Target AUC (6mg/mL/min) * [GFR + 25]


(25 = constant representing non-renal Cl)

Oxaliplatin

Uses: colorectal cancer, GI tumors




Often used in combo with 5-FU or Capecitabine




Dose: 135 mg/m^2

Oxaliplatin


(Adverse Effects)

Hypersensitivity rxn


*DLT: Neurotoxicity (acute and delayed)


Nephrotoxicity


Fatigue


Myelosuppression


N/V/D


Pulmonary Fibrosis *rare

Oxaliplatin


(DLT elaborated)

Acute Neurotoxicity: peripheral neuropathy, visual changes, auditory toxicity, *pharyngolaryngeal dysesthesia



Delayed Neurotoxicity: cumulative peripheral sensory neuropathy



Proph: Avoid cold temperatures and food/drink! (pharyngolaryngeal dysthesias)

Oxaliplatin


(N/V tx)

5-HT3 antagonist (setron drug) + dexamethasone




(ex: Ondasetron, Granisetron, Palonosetron, Dolasetron, Metaclopramide)

Busulfan


(Myleran)

Alkyl Sulfonate


Affect early WBC precursors


Uses: chronic myeloid leukemia (CML), BMT


Dosage Forms: oral



*Prolonged nadir time


AD: "Busulfan lung" = pulmonary fibrosis, seizures (proph. with phenytoin)

2nd Gen Nitrogen Mustards

Chlorambucil, Melphalan, Bendamustine




More stable with inclusion of 6-member ring and long hydrocarbon/carboxyl tail

Chlorambucil


(Leukeran)

Uses: chronic lymphocytic leukemia (CLL), non-Hodgkin's Lymphoma (NHL)




Dosage Form: 2 mg oral tabs


Dose every 2-4 weeks




AE: bone marrow suppression, N/V, pyrexia

Melphalan


(Alkeran)

Uses: multiple myeloma, BMT


Dosage Forms: oral and IV




9 mg/m^2 PO x4-7 days Q4-6 weeks




(BMT = 100 mg/kg)

Bendamustine


(Treanda)

Uses: Chronic lymphocytic leukemia (CLL), non-Hodgkin's Lymphoma (NHL)




AE: bone marrow suppression, N/V, pyrexia


(more than chlorambucil)

Topoisomerase Inhibitors


(Mechanism of Action)

Prevents Topoisomerase 1 or 2 from uncoiling the supercoiled DNA for transcription and reduplication




Topoisomerase 1 inhibitors: Camptothecins, Indolocarbazoles, Indenoiseoquinolines


Topoisomerase 2 inhibitors: Podophyllotoxins, Quinoxalines, Antibiotics

Irinotecan


(Camptosar)

Camptothecin (T1)


Uses: Colorectal cancer



AE: Diarrhea (acute and delayed), neutropenia (dose dependent), N/V, dehydration, alopecia, mucositis, acute pulmonary toxicity?

Irinotecan


(Diarrhea tx)

Acute:


- atropine 0.25 - 1 mg IVP




Delayed:


- loperamide 4 mg PO LD, then 2 mg PO Q2h ATC until resolved for 12 hours

Etoposide


(VP-16, Vepesid)

Epipodophylotoxin (T2)


Uses: Lung cancer, NHL, BMT



Dosage Form: in EtOH, IVPB (hypotension), 50 mg PO capsules (F= 50%)

5 Classes of Antitumor Antibiotics

1.) Cyclopropylpyrroloindole


2.) Minor-Groove DNA-binding


3.) Aminoquinone


4.) Polycyclic Aromatic (anthracyclines)


5.) Enediyne

2 Broad Classes of Antitumor Antibiotics

1.) Alkylate DNA


(Cyclopropylpyrroloindoles, minor groove


binding, aminoquinones)




2.) Redox Cycling


(Polycyclic aromatics, enediynes)

Redox Cycling Antibiotics


(Class Adverse Effects)

Cardiotoxicity

Bleomycin


(Blenoxane)

4 different proteins from bacteria




Uses: testicular, NHL, head/neck cancers




AE: pulmonary toxicity, pyrrexia, mucositis

Polycyclic Aromatics


(aka Anthracyclines)

Doxorubicin, Amrubicin, Epirubicin, Valrubicin, Pirarubicin, Berubicin




MOA: intercalates between DNA base pairs and generates free oxygen radicals using the carbonyls on its B ring

Doxorubicin


(Adriamycin)

Uses: solid and hematologic tumors




AE: cardiotoxicity (max = 550 mg/m^2 for life), myelosuppression, N/V/D, red urine, vesicant, alopecia, radiation recall, mucositis




Dose: 25-60 mg/m^2 IVP

Dexrazoxane


(Zinecard)

MOA: Metal Chelator




Uses: Cardioprotection in women with metastatic breast cancer who have received 300 mg/m^2 doxorubicin




AE: myelosuppression, N/V, alopecia, LFT elevation

Mitozantrone


(Novantrone)

Uses: breast cancer, NHL, acute leukemia, ovarian cancer, metastatic prostate cancer (+ prednisone)




AE: cardiomyopathy, N/V, alopecia (less than other anthracyclines), blue/green secretions




Dose: 10-12 mg/m^2 IVP or IVPB

Anti-Metabolites


(Classes and Subclasses)

1.) Anti-Folates


- Dihydrofolate Reductase inhibitors


- Thymidylate Synthase inhibitors


- Glycinaminde Ribonucleotide Formyl


Transferase inhibitors


- Dihydropteroate Synthase inhibitors


2.) Anti-Pyrimidines


- Uracil analogs


- Cytidine analogs


3.) Anti-Purines


- 1st and 2nd generation

Anti-Metabolites


(Mechanism of Action)

1.) Serve as false building blocks


2.) Inhibit synthesizing enzymes


- prevent synthesis of DNA and RNA




Non-selective, therefore best localized

Methotrexate


(Trexall, Rasuvo)

MOA: Anti-Folate (Dihydrofolate Reductase-i)




Uses: solid and hematologic tumors (ex: breast, lung, head/neck cancers, sarcomas)




Dosage Forms: injection including intrathecal


Dose: 12 mg/m^2

Methotrexate


(Adverse Effects + Risk Factors)

AE (dose dependent) myelosuppression, N/V, mucositis, hepatotoxicity, neuro/nephrotoxicityRisk Factors: renal dysfunction, prior use of nephrotoxins, pleural effusion, ascites, GI obstruction, poor hydration, acidic urine


Dose > 100/m^2 requires leucovorin rescue

Methotrexate


(Monitoring)

Low Risk:


T1/2: < 3.5 H


C24H: < 5 x 10^-6 M


Leucovorin = 10 mg/m^2 Q6H for 72H (standard low dose)



High Risk:


Monitor until < 1 x 10^-8 M and escalate leucovorin as needed

Fluorouracil


(5-FU)

Uses: GI tumors, colorectal cancer, pancreatic


2nd line in breast, lung and head/neck




Dose: 500-1000 mg/m^2 IVP or 24H CIVI

Fluorouracil


(Adverse Effects)

CIVI: mucositis, diarrhea, hand-foot syndrome


IVP: neutropenia


Elevated LFTs, coronary artery spasm, photosensitivity




Proph: Ice chips and oral hygiene (mucositis)


Loperamide or lotomil (diarrhea)