back-to-basics Dr Xinni Song 2015
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Transcript back-to-basics Dr Xinni Song 2015
Back to Basics
Oncology
April 1, 2015
Xinni Song MD FRCPC
University of Ottawa
Outline
Clinical epidemiology of Cancer
Cancer Risk Factors and Screening
Diagnosis and Staging
Treatments
Quiz
Epidemiology
Canadian Cancer Stats
More men than women are diagnosed with cancer
Between 1995-2005, overall cancer mortality has declined
Increasing incidence of cancer is mainly due to aging population
Over ¼ (27%) of all cancer death due to lung cancer
Canadian Cancer Statistics 2014
Canadian Cancer Statistics 2014
Canadian Cancer tatistics 2014
Proportion of death due to cancer and other causes , 2011
Quiz
Which cancer has the highest incidence?
In men?
Prostate Cancer
In women?
Breast cancer
Which cancer has the highest mortality rate?
In men?
Lung cancer
In women?
Lung cancer
Canadian Cancer Statistics 2014
10 most common cancers in men (percentage of all new cancers in men), Canada, 2011
Lung
14%
Colorectal
13%
Bladder
6%
Non-Hodgkin lymphoma
5%
Kidney
3%
Prostate
27%
Leukemia
3%
Melanoma
3%
All other cancers
21%
Oral
3%
Pancreas
2%
Data source: Canadian Cancer Statistics 2011
10 most common cancers in women (percentage of all new cancers in women), Canada, 2011
Lung
14%
Colorectal
11%
Body of Uterus
6%
Thyroid
5%
Non-Hodgkin lymphoma
4%
Breast
28%
Ovary
3%
Melanoma
3%
All other cancers
20%
Pancreas
3%
Leukemia
3%
Data source: Canadian Cancer Statistics 2011
Cells and Molecules
Neoplasm:
Characterized by growth and division of cells outside the
control of normal regulatory mechanisms
Cells have undergone permanent DNA damage
Characterized as benign or malignant by their capacity for
invasion and metastasis
Malignant tumours are divided most broadly into carcinomas
and sarcomas, and blastomas in children
Exceptions to the rule: Hepatoma, Glioblastoma, Melanoma,
Leukemia, lymphoma
This figure was adapted from Cell, Vol 100, Hanahan and Weinberg, The
Hallmarks of Cancer, pp 57-70, Copyright Elsevier (2000).
Genetic Changes
Cancers arise due to changes in a cell’s genetic machinery
Oncogenes
Tumour suppressor genes
Oncogenes eg. bcr-abl in CML
Genes have dominant transforming properties: one abnormal
copy is sufficient
Mutation or overexpression leads to unregulated cell division
Tumour Suppressor Genes eg. BRCA1/2, RB
Genes which are normally involved in the negative regulation of
cell cycling
Genes have recessive transforming properties: both copies
must be abnormal
loss of these genes function allows cells to proliferate
unregulated, or with reduced restraints
CRC Adenoma-Carcinoma Sequence:
Vogelstein’s model
Mutations can be inherited, or occur through exposures to
carcinogens
Carcinomas
Carcinomas
Arise from epithelium
Commonest are adenocarcinoma and squamous carcinoma
Many others, including germ cell tumours, transitional cell
carcinomas, neuroendocrine carcinoma
Adenocarcinoma
Breast
Lung
Prostate
Most GI, including colon
Endocrine malignancies
Carcinomas
Squamous carcinoma
Head and neck cancers
Lung
Skin
Cervix
Esophagus
anus
Germ Cell Tumours
Most commonly testicular cancers
Ovarian
Primary mediastinal
Histologic subtypes include teratomas, embryonal carcinomas,
yolk sac tumours
Sarcomas
Much rarer than carcinomas
Arise from mesenchymal tissue
About 800 soft-tissue sarcomas per year in Canada, and fewer bone
sarcomas
Named for the tissue they arise from, when known
Known tissues of origin
Liposarcoma
Rhabdomyosarcoma
Leiomyosarcoma
Osteosarcoma
Chondrosarcoma
Fat
Striated muscle
Smooth muscle
Bone
Cartilage
Unknown tissue of origin
Malignant fibrous histiocytoma, Ewing’s Sarcoma, alveolar soft part tumour
Summary
Histologic characteristics of cancer
Excessive cellularity
Disrupted architecture
Frequent mitoses
Unusual cell appearance
Large, hyperchromatic nuclei
Varying degrees of differentiation
Invasion into surrounding tissue
Cancer management
Screening
Diagnosis
Staging
Treatment
Screening
Screening is the routine testing of asymptomatic individuals
for the presence of cancer
Good screening strategy:
Test is acceptable to the target population
Risk is minimal and cost is reasonable
Test is accurate: high sensitivity and specificity
Test detects the disease in an asymptomatic (pre-clinical) phase
Evidence exists that treatment in the asymptomatic phase
improves outcomes
Screening test
Sn-n-out/Sp-p-in
Screening
Commonly screened cancers in adults are:
Breast (mammography)
Cervix (Pap smears)
Colon (FOBT/colonoscopy/sigmoidoscopy)
Prostate (PSA)
Evidence behind screening is surprisingly controversial, in
part because of the difficulty of designing studies to avoid
bias
Screening
Lead-time Bias
Cancer becomes incurable
Symptoms
Cancer
starts
Diagnosis and treatment
Time
Treatment
Diagnosis by screening
Death
Why Not Screen for All Cancers?
Cancer-related factors
Cancer Starts Symptoms
Incurable
Death
Preclinical interval too short
Incurable
Cancer Starts
Symptoms
Cancer incurable, even if screen detected
Death
Why Not Screen for All Cancers?
Test-related factors
Test not sensitive/specific enough
Test can’t be applied to whole population
Too expensive
Insufficient infrastructure/personnel
Unacceptable to majority of population
Tumour not common enough
Risk Factors for cancer
Factor Type
Attributable Risk
Environmental
5%
Lifestyle
45%
Occupational
4%
Pharmacologic
2%
Biologic
4%
Risk Factors for lung cancer
90% of all lung cancers are attributable to smoking
Including 2nd hand smoking
10% occur in non-smokers (younger, female, Asian)
Risk increases with # packs smoked, age at onset
Tobacco smoke has > 40 identified different carcinogens
Women are more susceptible to carcinogenic effects
Other risks include some occupational exposures
Asbestos, radon, sillica, chromium, arsenic
Risk factors for breast cancer
Hormonal and
Age and gender – older and female
reproductive risk
Race/ethnicity –
Early menarche
whites>blacks>hispanic/indians/asi
ans
Diet/Lifestyle
First birth at older
age
Absence of breast
feeding
Nulliparity
Late menopause
HRT
Post-menopausal obesity
Alcohol
Medical history
Ionizing radiation
Increased breast density
Benign breast lesions
Environmental
Risk factors for breast cancer
Family history and genetic risks
Breast cancer susceptibility gene 5-6% of all BC
BRCA1/2, p53, ATM, PTEN
BRCA mutations
BRCA1
75 % lifetime risk of breast cancer
50 % lifetime risk of ovarian cancer
BRCA2
75 % lifetime risk of breast cancer
25 % lifetime risk of ovarian cancer
Melanoma, laryngeal, colon, prostate, pancreas, lymphoma, leukemia
Colorectal Cancer : Risk Factors
Dietary – most important!
High fat, low fibre, high EtOH, low selenium, low calcium
Underlying Conditions
IBD, prior CRC or polyps, post-radiation
Hereditary – 5%
FAP (familial adenomatous polyposis) – 1/200, APC
gene
Gardener’s-intestinal polyps and osteomas
Turcot’s – familial polyposis and brain tumors
HNPCC (hereditary non-polyposis colorectal ca) 2-4%
Genetics: “microsatellite instability = MSI”, MSH2, MLH1,..
Peutz-Jeghers- polyps and pigmented lesions on oral
mucosa/lip
Family Hx – 10% have
Risk factor for colon cancer
Family History
General population 6% lifetime risk
One 1st degree relative: 12%
Two 1st degree relatives: 18%
1st degree relative <45 yrs old: 30-42%
Diagnosis
Early detection of cancer is the key
Recommend screening test if available
Systematically think about symptoms of cancer
Local symptoms of tumour
Symptoms from regional (nodal) spread
Symptoms from metastatic spread
Symptoms from paraneoplastic phenomena
Diagnosis
Local Symptoms
Lung
Cough, hemoptysis, SOB, chest wall pain
Prostate
Urinary obstruction, hematuria
Breast
Breast mass, skin changes, bleeding from nipple
Colon
Blood in stool, iron deficient anemia, change in bowel habits
Hematological
Symptoms of marrow replacement, cytopenias
Diagnosis
Symptoms from regional
Symptoms from Metastatic
(nodal) spread
Spread
Lung (mediastinal nodes)
SVCO, esophageal
obstruction, hoarse voice, etc
Liver
Jaundice, abnormal LFT, pain
Breast (axillary nodes)
Lump under arm
Brain
Focal neurologic symptoms,
seizures
Lung
Cough, SOB, hemoptysis
Bone
Pain, pathologic fracture,
elevated Alk Phos
Diagnosis
Paraneoplastic Syndromes
Common, non-specific
Poor appetite, weight loss, DVT
Hormonal syndromes
SIADH, Cushing’s, hypercalcemia, carcinoid
Neurologic syndromes
Lambert-Eaton Syndrome, demyelination syndromes
Diagnosis and Staging
Definitive diagnosis – tissue needed
Purposes of staging
Group similar patients together
Determine intent of treatment
Prognostic purposes
Most cancers are staged with a TNM staging system, which
leads to overall stage I-IV
Tumour
Nodal
Metastases
Treatment
Intent of Treatment
Radical vs. Palliative
Primary
Adjuvant
Neoadjuvant
Modalities of Treatment
Surgery
Radiotherapy
Systemic therapy
Treatment: Surgery
Indications for Surgery
Obtain tissue for diagnosis/staging
Definitive treatment of primary tumour
Palliation of obstructive/mass effect symptoms
Cancer prophylaxis in high-risk cases
Esophageal dysplasia/BRCA/FAP/ulcerative colitis
Support other procedures
Central venous access
Rehabilitation/reconstruction
Treatment: Radiation
Ionizing radiation delivered to tumour and surrounding
tissue
External Beam
Brachytherapy
Systemically administered agents
Radiation treatment intent
Curative as primary treatment
Adjuvant for local regional disease control
Palliative symptom management
External Beam Radiotherapy
Treatment: Systemic Therapy
Chemotherapy
Hormonal Therapy
Immunotherapy
Targeted therapy :Small molecules/monoclonal antibodies
Treatment: Chemotherapy
Mechanisms of action
Bind to DNA
Alkylating agents, platinum agents
Antimetabolites
5-FU, methotrexate
Bind to microtubules
Vinka alkylaoids, taxanes
Interfere with topoisomerase
Anthracyclines
Treatment: Chemotherapy
Acute toxicities
Mucositis/diarrhea
Nausea
Hair loss
Hypersensitivity reactions
Pain
Thromoboembolic events
Myelosuppression
Risk of febrile neutropenia
Fatigue
Chronic Toxicities
Infertility
Particularly alkylating agents
Leukemogenesis
Anthracyclines, alkylating
agents
Neurotoxicity
Cisplatin, taxanes, vinca
alkyloids
Nephrotoxicity
Cisplatin
Cardiotoxicity
anthracyclines
Treatment: Hormonal Therapy
Hormone sensitive cancers
Breast
Prostate
Endometrial
Ovarian
Tumours retain some characteristics of the original tissue
Treatment: Monoclonal Antibodies
Antibody
Trastuzumab (Herceptin)
Rituximab (Rituxan)
Cetuximab (Erbitux)
Bevacizumab (Avastin)
Tositumomab (Bexxar)
Ibritumomab (Zevalin)
Target
Tumour
HER-2
CD-20
EGFR
VEGF
CD-20 + I131
CD20 + Y
Breast
Lymphoma
Colon
Colon, Lung
Lymphoma
Lymphoma
Treatment: Small Molecules
Molecules developed to inhibit specific proteins/enzymes
responsible for malignant behavior
Imatinib (Glieevec)
Gefitinib (Iressa)
Erlotinib (Tarceva)
Lapatinib (Tykerb)
BRAF inhibitors
CML, GIST
Lung cancer
Lung cancer
Breast cancer
Melanoma (BRAF mutation+)
Treatment – Other
Palliative care
Pain and symptom management
End of life care
Cancer Survivorship
A rapidly expanding field, arising from the recognition that
people who have completed curative cancer therapy have
ongoing complex medical, social, psychologic issues
Lung Cancer - pathology
Lung Cancer: NSCLC
Stage I-II disease
Limited to lung and ipsilateral hilar nodes
Surgery gives ~50% long-term survival rate
Improved to ~60-65% with adjuvant chemotherapy
Stage III Disease
Lung and ipsilateral or contralateral mediastinal lymph nodes
Seldom amenable to surgery
Radiation alone can cure 7-12%
Adding chemotherapy increases rate to ~18-25%
Stage IV - Metastatic disease
Incurable, with median untreated survival of 4 months
With chemotherapy, median survival increases to 10 months
50% of patients have improved symptoms or QoL on chemo
Lung Cancer: Small Cell
Staged as either Limited or Extensive
Limited
Confined to one hemithorax/can be treated in one radiation portal
Treated with chemo and radiation, with a long-term survival rate of
~25%
Median survival untreated: 4 months treated: 12 months
Extensive
Beyond one hemithorax
Treated with palliative chemotherapy
Median untreated survival 6 weeks
Median treated survival 9 months
Breast Cancer - pathology
Invasive ductal carcinoma - 76%
Invasive lobular carcinoma – 8%
Ductal/lobular – 7%
Mucinous(colloid) – 2.4%
Tubular carcinoma -1.5%
Medullar carcinoma – 1.2%
Papillary carcinoma -1.0%
Other (micropapillar and metaplastic) – <5%
Breast Cancer Staging and Prognostic
Markers
TNM staging
T - tumor extent
N- nodal status
M- metatstatic disease
ER/PR receptor status
Histological grade, lymphvascular invasion
Her2 status (epidermal growth factor receptor)
Gene profiling
Breast Cancer Molecular
Classification
ER(-)
ER(+)
Solie et al. PNAS 2001; 98:10869-10874
Breast cancer treatment
Stage I-II
Primary therapy – surgery for the breast lesion + regional LN
Systemic therapy – chemotherapy/hormone/targeted therapy
Radiation therapy to breast/chestwall/LN
Stage III
Neoadjuvant systemic therapy
Surgery
Radiation therapy
Stage IV – metastatic
Systemic therapy
Surgery/radiation as symptom management tools
Adjuvant Endocrine Therapy
Inhibition of Estrogen-dependent Growth
Tamoxifen
Estrogen
biosynthesis
Nucleus
Estrogen
biosynthesis
Aromatase
Inhibitors
Estrogen
Estrogen Receptor
Bhatnagar AS, et al. J Steroid Biochem Mol Biol. 2001;77:199-202.
Inhibition
of growth
Tumour
cell
EBCTCG overview – tamoxifen vs. not
Benefits of Chemotherapy
Polychemotherapy significantly reduces the risk of recurrence
and death
Absolute benefit is bigger in patients
Under age 50
With ER- tumors
With Node(+) disease
Polychemotherapy regimens longer than 6 months do not
appear to improve survival
1Early
Breast Cancer Trialists’ Collaborative Group. The Lancet 352:930-942
Metastatic disease
bone > lung > liver > brain
Most commonly detected in first 5 years after definitive
treatment
Treatments try to improve survival and quality of life
Median overall survival from time of diagnosis: 2-3 years
5y survival: 5-10%
10y survival: 2-5%
Age, disease free interval, # and location of mets, ER status, her2
status
Factors Determining choice of
Treatment in Advanced Breast Cancer
Choice of
Treatment
Tumour
Characteristics
Receptors
Sites of
disease
Disease
Burden
Patient
Characteristics
Performance
Status
Age
Previous
therapy
Patient
preference
Treatment
options
Toxicity
Colon Cancer
Stage I-III
Typically treated by surgery, with long-term control rates of 40-
85%, depending on stage
Adjuvant chemotherapy decreases relative risk of recurrence by
30%, usually offered to pt with stage III or high risk stage II
Adjuvant chemo and radiation often used together in rectal,
rather than colon cancers
Stage IV
Palliated by chemotherapy, radiation as indicated
Untreated survival ~4-6 months
Optimally treated survival ~24 months
Prostate Cancer
Early stages maybe treated with surgery or radiation
More advanced disease is treated with some combination of
radiation and hormone therapy (androgen deprivation)
Chemotherapy has a limited role, usually just for metastatic
disease after hormones fail
Q: A unilateral vocal cord paralysis is common in the
setting of a mediastinal mass and lung cancer, which
vocal cord is more commonly involved?
Left vocal cord is more commonly - compression of the left
recurrent laryngeal nerve
Q: What are the five most common tumors to
metastasize to skin ?
breast, lung, ovary, colon, kidney
Q: What is the most common location of
metastasis for renal cell carcinoma?
Lung
Q: Neutropenic fever is found in 30-40% of
patients what is the most common etiology?
Gram positive bacteria
Q: What syndrome causes diarrhea, flushing,
bronchospasm and right sided heart failure?
Carcinoid syndrome
Q: EKG findings in cardiac tamponade
sinus tachycardia, electric alternans, low QRS voltage
Q: What is the term used for tumor at the apex of
the lung or superior sulcus which may involve
brachial plexus, sympathetic ganglion, vertebral
bodies, leading to pain, upper extremity weakness
and horner’s syndrome?
Pancoast tumor
Q:What is the most common paraneoplastic
syndrome associated with renal cell carcinoma?
hypercalcemia (20%)
Q: What is the most common pulmonary
malignancy associated with hypercalcemia?
Squamous cell carcinoma of the lung
Q: Multiple endocrine neoplasia
MENI - pancreatic tumors, pituitary adenoma, parathyroid
hyperplasia
MEN II – parathyroid hyperplasia, medullary thyroid
carcinoma, pheochromocytoma, multiple mucosal neuromata
Q: Which malignancy is seen at increased
frequency in people working in the ruber industry?
Bladder cancer - related to exposure to aromatic amines
Q: What cancer is associated with Barrett’s
esophagus?
Adenocarcinoma of the esophagus
Q: what is the most common solid malignancy in
males aged 15-35?
Testicular cancer
Q: Tumor markers
Breast cancer CA15-3, CA27-29m and CEA
Ovarian cancer CEA, CA-125
Testicular cancer b-HCG, AFP
Hepatocellular carcinoma AFP
Q: What is Li-Fraumeni Syndrome?
High familial incidence of tumors of soft tissue, breast, brain,
bone, leukemia, and adrenal cortex
Q: What chromosomal abnormality is associated
with young men with malignant mediastinal germ
cell tumors
Kleinfelter’s syndrome
Q: Paraneoplastic syndrome commonly
associated with small cell lung cancer
SIADH
Hypercalcemia
Ectopic ACTH
Eaton-Lambert Syndrome