Transcript back-to-basics Dr Xinni Song 2014

Back to Basics
Oncology
March 31, 2014
Xinni Song MD FRCPC
University of Ottawa
Outline
 Clinical epidemiology of Cancer - How Big is the Problem?
 Cancer Risk Factors and Screening
 Diagnosis and Staging
 Treatments
 Quiz
Cancer Epidemiology
Canadian Cancer Stats
 More men than women are diagnosed with cancer 51.7% vs 48.3%
 Over ¼ (27%) of all cancer death due to lung cancer
 Between 1995-2005, overall cancer mortality has declined
 Increasing incidence of cancer is mainly due to aging population
Proportion of deaths due to cancer and other causes, Canada, 2007
Other, 23.1%
Cancer, 29.6%
Kidney disease, 1.6%
Suicide, 1.5%
Alzheimer's disease,
2.5%
Influenza and
pneumonia, 2.3%
Diabetes, 3.1%
Diseases of the heart,
21.5%
Accidents, 4.2%
Chronic lower
respiratory diseases,
4.5%
Cerebrovascular
diseases, 5.9%
Adapted from: Ten leading causes of death, Canada, 2007, Statistics Canada
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
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 causes of cancer death in men (percentage of all cancer deaths in men),
Canada, 2011
Colorectal
13%
Lung
28%
Bladder
3%
Non-Hodgkin
lymphoma
4%
Kidney
3%
Leukemia
4%
Pancreas
5%
Prostate
10%
Stomach
3%
All other cancers
23%
Data source: Canadian Cancer Statistics 2011
Esophagus
4%
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
10 most common causes of cancer death in women (percentage of all cancer deaths in women),
Canada, 2011
Lung
27%
Colorectal
12%
Non-Hodgkin lymphoma
4%
Ovary
5%
Pancreas
6%
Breast
15%
Leukemia
3%
All other cancers
22%
Body of Uterus
2%
Brain
2%
Stomach
2%
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
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, large cell carcinoma, 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 parts 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)
CML, GIST
Lung cancer
Lung cancer
Breast cancer
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 palliatively with 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: 18-24 months
 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 asscociated 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, leuemia, 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
assoicated with small cell lung cancer
 SIADH
 Hypercalcemia
 Ectopic ACTH
 Eaton-Lambert Syndrome