Cancer Concepts – Winter, 2011

Final Review

CC-Pieters & Liebmann Feb 11 2011

What We’ll Try to Cover: Important
Points to Know
• What agents can cause cancer?
• How do cancer cells develop from normal cells?
• What is the difference between hyperplasia, metaplasia, dysplasia, carcinoma in situ,
invasive cancer, and neoplasia?
• What is an oncogene? Know some examples of oncogenes and how they function.
• What is a tumor suppressor gene? Know some examples of tumor suppressor genes
and how they function.
• What pathologic changes do cells undergo as they transform from normal to cancer?
• What are protein kinases?
• What is involved in the process of metastasis?
• What
Wh t iis angiogenesis
i i andd why
h do
d cancers needd it?
• Do cancer metastases pop up randomly? If not, know some sites that some tumors like
to go to.
• What are the major
j reasons that surgery
g y is used when approaching
pp g cancer?
• What are the major reasons that radiation is used when approaching cancer?
• What are the major reasons that drugs are used when approaching cancer?
CC-Pieters & Liebmann Feb 11 2011
What We’ll Try to Cover: Important
Points to Know ((continued))
• Have a general understanding of chemotherapy drugs by class – alkylators, anti-
metabolites,
b li topoisomerase
i inhibitors,
i hibi microtubule
i b l binding
bi di drugs,
d platinum
l i
analogues, immune therapies, antibodies, tyrosine kinase inhibitors, others
• What is the role of palliative care in cancer treatment?
• What interventions work to prevent cancer? How do they work?
• What cancer screening techniques are effective? What makes a cancer screen an
effective screen?
• What is the difference between stage and grade of cancer? Have a general sense of
stages
t off cancer
• How is pediatric oncology different from adult oncology?
• What long term health issues might survivors of cancer have to deal with?
• How can yyou explain
p differences in the incidence of cancer around the world?

CC-Pieters & Liebmann Feb 11 2011

Agents That Cause Cancer

 Chemical – Tobacco, Solvents, Pesticides

 Physical – Asbestos, Chronic Irritation
 Radiation – UV, Ionizing
 Viral – HPV, HIV, EBV, HTLV-I
 Bacterial – H.Pylori
 Parasitic – Schistosomes, Liver Flukes
 Think about how these cause cancer!

CC-Pieters & Liebmann Feb 11 2011

How Do
H D Cancer
C Cells
C ll Develop
D l
From Normal Cells?

 Acquisition of Genetic Changes

– Loss of Tumor Suppressor Function
 Common – TP53, Rb
– Activation of Oncogene Function
 Common – TEL, EGFR, HER2, KRAS, MYC, etc.
 Morphologic
p g Changes
g
– Normal → Hyperplasia → Dysplasia → CIS →
Invasion

CC-Pieters & Liebmann Feb 11 2011

Whatt is
Wh i the
th difference
diff between
b t
hyperplasia, metaplasia, dysplasia,
corcinoma in situ
situ, invasive cancer
cancer,
and neoplasia?
 Hyperplasia
H l i –Increase
I in
i Number
N b off CCells
ll
 Metaplasia –Transformation of One Cell Type Into
Another
 Dysplasia –Abnormal Development of Cells
 Carcinoma in situ–Malignant Cells That Have Not
Invaded Into Tissue
 Invasive Cancer – Malignant Cells That Have Invaded
Into Tissue and Can Spread Further
 Neoplasia
p – New Cell Growth – Does Not Necessarilyy
Refer to Benign or Malignant
CC-Pieters & Liebmann Feb 11 2011
What is an oncogene?
Know some examples of oncogenes
and
d how
h they
th function.
f ti
 Normal Genes (Proto-Oncogene)
(Proto Oncogene) Vital to
Normal Cell Growth
 Normal Functions:
– Growth Factors (sis–B Chain of PDGF)
– Receptors (erb-2–HER2, EGFR)
– Intracellular Signal Transduction (src, abl, KRAS)
– Nuclear Transcription Factors (myc, hox)

CC-Pieters & Liebmann Feb 11 2011

What is a tumor suppressor gene?
Know some examples of tumor
suppressor genes and how they
function.
 Normal Function Blocks Cell Proliferation
 Normal Function Leads To DNA Repair
 Normal Function Leads to Apoptosis
 Examples – Rb, TP53, APC

CC-Pieters & Liebmann Feb 11 2011

What pathologic changes do cells
undergo as they transform from
normal to cancer?
 Morphologic Changes
– Normal → Hyperplasia → Dysplasia → CIS →
Invasion
 Terms to Describe Morphology Changes
– Pleomorphism
– N:C Ratio
– Condensed Chromatin
– Loss of Polarityy
– Anchorage Independent Growth
– Loss of Contact Inhibition CC-Pieters & Liebmann Feb 11 2011
What Are Protein Kinases?
 Kinases add phosphate (PO3=) to proteins
 Tyrosine, Serine, Threonine are amino
acids that are phosphorylated
 Large
g ((MW=80), ), charged
g PO3= induces
conformational change on protein
 Conformational change g affects p
protein
function
 ATP or GTP are PO3= donors
 Protein kinases are drug targets
CC-Pieters & Liebmann Feb 11 2011
What is involved in the process of
metastasis?
 Cellular Discohesion–Cells arenormally anchored to basement
membranes, the extra-cellular matrix, and adjacent cells. These
connections need to be lost or broken broken.
 Invasion Through Basement Membrane –The basement membrane must
be destroyed. This will require enzymes. To get through the basement
membrane, theremust be cell motility.
 Invasion Into Blood/Lymphatic Vessel –Vessel Vessel walls need to be breached
breached.
 Survival in Blood/Lymph –The cancer cell must avoid immune surveillance
 Exit From Blood/Lymphatic Vessel –See “Invasion into
blood/lymphaticvessel”
 Growth in “Foreign Soil” –Metastasis necessarily means the ability to grow
in an environment that is foreign to the one the cell originated in. There
must be an ability to tolerate and thrive in new conditions.
 Recruitment of New Vasculature –In the absence of blood vessels, growth
off a colony
l off cells
ll iis lilimited
it d b
by th
the diff
diffusion
i off oxygen andd nutrients.
ti t

CC-Pieters & Liebmann Feb 11 2011

Whatt is
Wh i angiogenesis
i i and
d why
h do
d
cancers need it?

● 450 µm Hepatoma Cell

Spheroid

● Green Cells At Rim Are Viable

● Red Cells in Center are

Necrotic

NO Blood Flow = NO Life

Molecular Therapy (2009) 17 8, 1404–1410

CC-Pieters & Liebmann Feb 11 2011
What is angiogenisis and why do
cancers need it?
Degradation of Basement
Membrane of Existing
Vessel

Migration of Endothelial
Cells into Interstitium

Endothelial Cell Proliferation

Lumen Formation

Generation of New
Basement Membrane

Fusion of Newly Formed

Vessels
CC-Pieters & Liebmann Feb 11 2011
Do cancer metastases pop up
randomly? If not, know some sites
th t some tumors
that t like
lik tto go tto.
 Cancer Metastases Do NOT Appear at Random
 Preferred Sites of Spread for Selected Cancers:
– Lung Cancer: Bones, Liver, Adrenal Glands, Brain
– Breast Cancer: Bones
Bones, Lung,
Lung Liver,
Liver Brain
– Colon Cancer: Liver, Abdominal Cavity, Lungs
– Prostate Cancer: Bones
– Pancreatic Cancer: Liver, Abdominal Cavity
– Renal Cell Carcinoma: Lungs, Bones, Brain

CC-Pieters & Liebmann Feb 11 2011

Whatt are th
Wh the major
j reasons that
th t
surgery is used when approaching
cancer?
 Biopsy for Diagnosis
 Complete Resection for Cure
– R0: Complete Resection, Negative Margins
– R1: Grossly Complete Resection
Resection,
Microscopically Positive Margins
– R2: Grossly Incomplete Resection
 Metastatectomy – Possibly for ?Cure?
 Palliation
– Relief of Obstruction, Bleeding, Pain, etc.
CC-Pieters & Liebmann Feb 11 2011
What are the major reasons that
radiation isused when approaching
cancer?
 “Radical Radiation for Cure
 Adjuvant Radiation After Surgery
– Improve Local Control
– Improve Survival
 Palliative Radiation
– Pain Control
– Control Bleeding
– Open
p Airways y
– ?Prolong Life? (Cranial Radiation for Mets)
CC-Pieters & Liebmann Feb 11 2011
Whatt are th
Wh the major
j reasons that
th t drugs
d
are used when approaching cancer?

 Curative Chemotherapy
– Leukemia, Lymphoma, Germ Cell Cancer
 Adjuvant Chemotherapy
– Improve Survival After Surgical Resection
– Improve Survival When Given With Radiation
 P lli ti Ch
Palliative Chemotherapy
th
– Relieve Pain, Dyspnea, Performance Status
– Modestly Improve Life Span

CC-Pieters & Liebmann Feb 11 2011

Have a general understanding of
chemotherapy drugs by class –
alkylators, anti-metabolites,
topoisomerase inhibitors, microtubule
bi di d
binding drugs, platinum
l ti analogues,
l
immune therapies, antibodies, tyrosine
kinase inhibitors,
inhibitors others

 Mechanism
M h i off A
Action
ti
 Metabolism
 Toxicity
CC-Pieters & Liebmann Feb 11 2011
Classes and
Cl d Mechanisms
M h i off
Chemotherapy Drugs

 Alkylators: Cyclophosphamide, Nitrogen Mustard

 Anti-metabolites: Fluorouracil (Capecitabine),
Cytarabine, Gemcitabine, Methotrexate, Fludarabine
 T
Topoisomerase
i I hibit
Inhibitors: Doxorubicin,
D bi i Etoposide,
Et id
Irinotecan
 Microtubule Binding Drugs: Vincas, Taxanes

CC-Pieters & Liebmann Feb 11 2011

Classes and
Cl d Mechanisms
M h i off
Chemotherapy Drugs

 Immune
u e Therapies:
e ap es Interferon,
te e o , IL-2
 Antibodies: Trastuzumab, Cetuximab, Rituximab
 TK Inhibitors: Erlotinib, Sunitinib, Lapatinib
 Platinum Compounds: Cisplatin, Carboplatin,
Oxaliplatin
 Hormonal Agents
Agents: Tamo
Tamoxifen,
ifen Aromatase Inhibitors
(Anastrazole), LHRH Agonists

CC-Pieters & Liebmann Feb 11 2011

Metabolism of Chemotherapy Drugs

 Primarily Renal – Platinum Analogues, Methotrexate,

Bl
Bleomycini
 Primarily Hepatic – Taxanes, Vincas, Anthracyclines,
Camptothecins TKIs
Camptothecins,
 Primarily Intracellular – 5-FU, Gemcitabine,
Cytarabine, Fludarabine
 Also – Prodrugs
– Cyclophosphamide, Capecitabine, Irinotecan,
Tamoxifen

CC-Pieters & Liebmann Feb 11 2011

Toxicity of Chemotherapy Drugs

 Myelosuppression – Common
– Exceptions:
E ti Vi
Vincristine,
i ti Bleomycin,
Bl i TKI
TKIs,
Antibodies, Cisplatin
 Nausea – Cisplatin,
Cisplatin Nitrogen Mustard
Mustard, Doxorubicin,
Doxorubicin
Nitrosureas
 Renal – Cisplatin
 Neurotoxicity – Vincristine, Taxanes, Cis-/Oxalo-
platin
 Cardiac – Doxrubicin,
Doxrubicin Trastuzumab

CC-Pieters & Liebmann Feb 11 2011

What is the role of palliative care
in cancer treatment?

 Should be employed throughout the disease –

not just at the end
 Relieve symptoms of disease and treatment
 Focus on prognosis
 Focus on patient’s
patient s goals

CC-Pieters & Liebmann Feb 11 2011

What interventions work to prevent
cancer? How do they work?

• Tobacco Cessation
• Diet and Cancer
– No evidence for supplements
• Surgery to Prevent Cancer
– In cancer family syndromes
• Drugs to Prevent Cancer
– Finasteride: Prostate Cancer
– Tamoxifen,
Tamoxifen Raloxifene: Breast Cancer
• Vaccines to Prevent Cancer
– Hepatitis B: Hepatocellular Cancer
– Papilloma
p Viruses: Cervical,, Head and Neck Cancers

CC-Pieters & Liebmann Feb 11 2011

What cancer screening techniques are
effective? What makes a cancer
screen an effective screen?
 Definitely Effective Screens
– Mammogram for Breast Cancer
– Colonoscopy, Fecal Occult Blood for Colorectal Cancer
– Pap Smear for Cervical Cancer
 Maybe Useful Screens
– Chest CT in Smokers for Lung Cancer
– Liver Scan/AFP in HB/CV(+) ( ) for Hepatoma
p
 Definition of Effective Screen
– Reduces Morbidity and Mortality of Screened Cancer,
NOT Just Able to Find the Cancer at an Early Stage

CC-Pieters & Liebmann Feb 11 2011

 What is the difference between stage and grade
of cancer? Have a general sense of stages of
cancer.

• Staging • Grading
– Films, Physical Exam – Histology
– Macroscopic Extent – Microscopic Appearance
– Strong Prognostic Value – Some Prognostic Value
– Strong Therapeutic Value – Little Therapeutic Value
– Uses T, N, M System – Uses Morphologic Guidelines

CC-Pieters & Liebmann Feb 11 2011

Staging Generalities

• Stage I – Small Tumor, Negative Nodes

• Stage II – Larger Tumor or Tumor Invades Deeper
Structures, Negative Nodes or Only Immediate Nodal
Groupp
• Stage III – Larger Tumor or Positive Nodes
• Stage IV – Distant Metastatic Disease

• There Are Exceptions To The Above Guide!

CC-Pieters & Liebmann Feb 11 2011

How iis pediatric
H di t i oncology
l different
diff t
from adult oncology?

 Different Cancers
– Few Carcinomas, More Leukemias
 Prediliction for Cancer at Unique Ages
– Growth
G hS
Spurts
 Less Association With Environmental Factors
 Stage Much Less Important
 Cancer is Less Common

CC-Pieters & Liebmann Feb 11 2011

What long term health issues might
survivors of cancer have to deal with?

 Increased Risk of Second Cancers

– Smoking,
Smoking Other Carcinogen
– ?Elevated Genetic Risk?
 Long-Term Side Effects of Treatment
– Chemotherapy – Heart Failure, Leukemia, Sensory
Neuropathy, Renal Insufficiency, Sterility, Pulmonary
Fibrosis,, etc.
– Radiation – Dementia, Sarcomas, Leukemia, Growth
Retardation, Dry Mouth, Strictures, etc.
– Surgery
S – Lymphedema,
L h d M
Malabsorption,
l b ti M
Maintenance
i t off
Stomas, Dyspnea, etc.
CC-Pieters & Liebmann Feb 11 2011
How can you explain
H l i differences
diff in
i the
th
incidence of cancer around the world?

 Different Environmental Exposures

– Infections
I f ti
 HBV and Hepatoma in Asia
 EBV and Burkitt’s Lymphoma in Africa
– Diets
 Esophageal Cancer Belt → Caspian Sea to China
– Introduction of Smoking
 Relatively New in Third World
– Local Habits
 Betel
B t lNNuts
t
 Access to Health Care
– Cervical Cancer in Third World CC-Pieters & Liebmann Feb 11 2011
Final Thoughts

 Relax
 Get a Good Night’s Sleep
 concept ((ˈkɒnsɛpt)
kɒnsɛpt) — n 1.
1 an idea
idea, esp an
abstract idea
– Obsess Less Over Trivia
– Worry More About Understanding the Concepts

CC-Pieters & Liebmann Feb 11 2011