Transcript Oncology Dr Garth Nicholas 2010

Back to Basics
Oncology
13 April 2010
Garth Nicholas
Outline
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How Big A Problem?
Cells and Molecules
Risk Factors and Screening
Diagnosis and Staging
Treatments
Specific Cancers
How Big A Problem?
• 171000 new cancers in Canada in 2009
• 75300 cancer deaths in 2009
• Projected to be the commonest cause of
death in Canadians in 2010.
How Big A Problem?
• Lifetime risk of developing cancer for Canadians
– Women 38%
– Men
43%
• 31% of PYLL due to cancer (954 000 years)
• 65% of diagnoses and 80% of deaths are in
people over the age of 60
• ~7500 cases (4.4%) in people younger than 20
Canadian New Cases and Deaths
Tumour
New Cases Deaths
Prostate
Lung
25500
23400
4400
20500
Case-Fatality
Rate
0.17
0.94
Breast
22900
5400
0.24
Colon
22000
9100
0.41
NHL
7200
3200
0.44
Women
Men
Women
Men
Cells and Molecules
• Cancer:
– Characterized by growth and division of cells
outside the control of normal regulatory
mechanisms
– Characterized as benign or malignant by their
capacity for metastasis
– Benign tumours designated by the suffix -oma
– Malignant tumours are divided most broadly
into carcinomas and sarcomas, and
blastomas in children
• Exceptions to the nomenclature rules:
– Hepatoma
– Melanoma
– Leukemia
– Glioblastoma
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
Carcinomas
• Adenocarcinoma
– Breast
– Lung
– Prostate
– Most GI, including colon
– Endocrine malignancies
– Characterized by gland formation
Carcinomas
• Squamous carcinoma
– Head and neck cancers
– Lung
– Skin
– Cervix
– Esophagus
– Anus
Carcinomas
• 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 parenchymal tissue
– About 800 soft-tissue sarcomas per year in
Canada, and fewer bone sarcomas
– Named for the tissue they arise from, when
known
Sarcomas
– Known tissues of origin
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•
•
•
•
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
Others
• Hematologic malignancies
– Do not fit well into the carcinoma/sarcoma
spectrum
– Technically, lymphomas are considered
sarcomas (reticulosarcoma) while leukemias
are considered carcinomas
– Practically, no one makes this distinction
Blastomas
Aggressive childhood tumours
– Neuroblastoma, retinoblastoma,
medulloblastoma
– Named for their histologic resemblance to
cells at the centre of blastocytes
Summary
• Histologic characteristics of cancer
– Excessive cellularity
– Disrupted architecture
– Frequent mitoses, sometimes bizarre
– Unusual cell appearance
• Large, hyperchromatic nuclei
– Varying degrees of differentiation
– Invasion into surrounding tissue
Genetic Changes
• Cancers arise due to changes in a cell’s
genetic machinery
• These changes involve genes that are
divided into two major groups
– Oncogenes
– Tumour suppressor genes
Genetic Changes
• Oncogenes
– Are altered forms of normal genes called
proto-oncogenes
– Genes have dominant transforming
properties: one abnormal copy is sufficient
– Proto-oncogenes tend to function in normal
cell cycling and differentiation
– Mutation or overexpression leads to
unregulated cell division
Genetic Changes
• Tumour Suppressor Genes
– Genes which are normally involved in the
negative regulation of cell cycling
– Genes have recessive transforming
properties: both copies must be abnormal
– Classic example is retinoblastoma
– Loss of these genes allows cells to proliferate
unregulated, or with reduced restraints
Genetic Changes
• CML is driven by the
bcr-abl oncogene
(Philadelphia
chromosome)
Genetic Changes
Genetic Changes
• In reality, single mutations are usually
insufficient for malignant transformation,
and cancer cells contain a number of
genetic abnormalities, many of uncertain
significance
• Hematologic cancers have fewer genetic
abnormalities than solid tumours
Risk Factors
• Risk factors for cancer are difficult to study
– Long interval between exposure and disease
– Many exposures to agents of unknown
significance
– Unclear correlation between carcinogenesis in
laboratory and in real world
• ?Threshold levels for carcinogenesis
– IARC publishes a list of known causes of
cancer, and estimates of their significance
Risk Factors
Factor Type
Attributable Risk
Environmental
5%
Lifestyle
45%
Occupational
4%
Pharmacologic
2%
Biologic
4%
Risk Factors
• Environmental Causes
– Aflatoxin
– Erionite
– Radon
– Solar Radiation
Hepatocellular carcinoma
Mesothelioma
Lung (RR=2)
Melanoma (RR=3)
Risk Factors
• Lifestyle Causes
– Tobacco
Lung (RR=12) Larynx (12) Oral
cavity (5), esophagus(4), kidney
(3), bladder (3), pancreas (2)
– Smokeless tobacco
Oral Cavity (2)
– Betel and tobacco
Oral Cavity (9)
– Alcohol
Oral cavity (5), esophagus(4),
larynx (3) liver (3)
– Diet
Risk Factors
• Occupational (35 factors listed)
– Benzene
– Asbestos
Leukemia (RR=3)
Mesothelioma (6), lung (3)
• Pharmacologic (18 factors listed)
– Alkylating agents (9)
– Immunosuppressants(2)
– Hormones (5)
– Others (2)
Leukemias
Lymphomas
Endometrium
Risk Factors
• Biologic Causes
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EBV
Burkitt’s lymphoma (RR=30)
H. pylori
Gastric (4)
HBV
Liver (100)
HCV
Liver (20)
HIV
KS (1000), NHL (100)
HPV t16,18 Cervix (20)
HTLV-1 Adult T-cell lymphoma (4)
O. viverrini
Cholangiocarcinoma (5)
S. haematobilium
Bladder (5)
Screening
• Screening is the routine testing of
asymptomatic individuals for the presence
of cancer
• Underlying screening is the assumption
that cancers detected at the asymptomatic
stage are more amenable to therapy
Screening
• Cancers commonly screened for in adults
are:
– Breast (mammography)
– Cervix (Pap smears)
– Colon (Barium enema/colonoscopy/FOBT)
– Prostate (PSA)
• Evidence behind screening is surprisingly
contentious, 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
Screening
• Length Time Bias
*
*
*
*
*
*
*
*
*
1
2
3
4
Screening
• Breast
– Recommendations are for annual breast
exam and biannual mammography starting at
age 50 (?ending at age 74)
• Cervix
– Recommend Pap smears annually for first
three years after becoming sexually active,
then every two years until age 70
– Frequency is different if any test is abnormal
Screening
• Prostate
– Ontario guidelines state that “Healthy men
without symptoms may decide to have a PSA
test after talking to their family doctor or if they
are at high risk for prostate cancer ("first
degree" relatives with the disease, men of
African ancestry).”
– Not covered by OHIP because no trial has
ever shown a survival advantage to screening
Screening
• Colon
– Methods include fecal occult
blood testing (FOBT),
colonoscopy, Ba enema,
sigmoidoscopy
– Ontario is currently running
a pilot program of FOBT in
12 areas to inform eventual
development of a provincewide policy
– Colonoscopy is widely used
despite paucity of evidence
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
Diagnosis
• Impossible to list all possible symptoms of
cancer
• Systematically think about symptoms in
four categories:
– 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
– Leukemia
• Symptoms of marrow replacement, cytopenias
– Breast
• Breast mass, bleeding from nipple
Diagnosis
• Symptoms from regional (nodal) spread
– Lung (mediastinal nodes)
• SVCO, esophageal obstruction, hoarse voice, etc
– Breast (axillary nodes)
• Lump under arm
Diagnosis
• Symptoms from Metastatic Spread
– Liver
• Jaundice, abnormal LFT, pain
– 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
• Ultimately, diagnosis requires tissue
– Fine needle aspirate
– Core biopsy
– Excisional biopsy
– Open biopsy
Staging
• The second part of diagnosis is staging
• Purposes of staging
– Group similar patients together
– Determine intent of treatment
– Prognostic purposes
• Standard staging tests vary by cancer, but
may include bone scans, marrow biopsy,
imaging of brain/thorax/abdomen
Staging
• Most cancers are staged with a TNM
staging system, which leads to overall
stage I-IV
– Tumour
– Nodal
– Metastases
Staging
• Breast Cancer
T1
T2
T3
T4
1-20 mm
20-50 mm
>50 mm
Chest wall, skin,
or inflammatory
N0
N1
N2
N3
No Nodes
Mobile axillary nodes
Fixed Axillary Nodes
Internal Mammery Nodes
M0
M1
No distant metastases
Distant metastases present
Staging
T
1
1
2
2
3
3
Any
4
Any
Any
N
0
1
0
1
0
1
2
Any
3
Any
M
0
0
0
0
0
0
0
0
0
1
Stage
1
2A
2A
2B
2B
3A
3A
3B
3B
4
Only people who work with cancer every day actually memorize these.
Staging
• Another staging system worth remembering is the Ann
Arbour stages for Hodgkin’s disease
Stage
I
II
III
IV
Suffix
Definition
Involvement of a single node region
Two or more node regions on same side of diaphragm
Lymph node regions on both sides of the diaphragm
Involvement of one or more extranodal sites in addition to the
site for which the suffix “E” is used (see below)
A
B
E
X
Absence of “B Symptoms”
Presence of “B Symptoms”: fever, drenching night sweats,
loss of >10% body weight in preceeding 6 months
Involvement of single extranodal site contiguous with nodal
disease
Bulky disease (nodal mass >10 cm, or mediastinum widened
>1/3)
Treatment
• Intent of Treatment
– Radical vs. Palliative
– 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: Surgery
• Surgery has a central role, as 90% of solid
tumours that are cured have surgery as
part of the treatment plan
• Appropriate primary cancer surgery
includes resection of primary tumour and
associated lymphatic drainage
• Surgical debulking is appropriate in only a
tiny minority of cases
– Ovarian cancer, Burkitt’s lymphoma
Treatment: Surgery
• In few cases is it appropriate to resect
metastatic disease:
– Solitary brain metastases
– Anatomically amenable liver metastases from
colon cancer
– Pulmonary metastases from sarcomas
– Residual disease in germ cell tumours
Treatment: Radiation
• Ionizing radiation delivered to tumour and
surrounding tissue
– External Beam
– Brachytherapy
– Systemically administered agents
• Not understood exactly how radiation causes
cell death
– DNA likely target
– Differential ability of tumour and normal cells to repair
radiation damage
Brachytherapy
External Beam Radiotherapy
Treatment: Radiotherapy
• Long-Term Complications
– Most related to long-term microvascular
changes
– Radiation pneumonitis/pulmonary fibrosis
– Demyelination/memory changes/dementia
– Infertility
– Second cancers
Treatment: Systemic Therapy
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•
•
•
Chemotherapy
Hormonal Therapy
Immunotherapy
Small molecules/monoclonal antibodies
Treatment: Chemotherapy
• Based on the (now disproved) notion that
cancer cells divide more rapidly than
normal cells
• Chemotherapy drugs tend to interfere with
a cell’s ability to divide normally
• Cells which cannot divide normally should
undergo apoptosis
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
– Myelosuppression
• Risk of febrile neutropenia
Treatment: Chemotherapy
• Chronic Toxicities
– Infertility
• Particularly alkylating agents
– Leukemogenesis
• Anthracyclines, alkylating agents
– Neurotoxicity
• Cisplatin, taxanes, vinca alkyloids
– Nephrotoxicity
• Cisplatin
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 (Glivec)
– Gefitinib (Iressa)
– Erlotinib (Tarceva)
– Lapatinib
CML, GIST
Lung cancer
Lung cancer
Breast cancer
Treatment
• 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
• Divided into:
– Non-small cell – 85%
• Adenocarcinoma
– Bronchoalveolar carcinoma
• Squamous
• Large Cell
– Small cell – 15%
Lung Cancer: NSCLC
• Typically staged by CT thorax, abdo,
head, bone scan, and mediastinoscopy if
surgery is considered
• 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
Lung Cancer: NSCLC
• 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 ~1825%
– Treatment can be difficult, and many patients
are not candidates
Lung Cancer: NSCLC
• Stage IV
– Metastatic disease
– Incurable, with median untreated survivals 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
• Treated with chemo and radiation, with a long-term
survival rate of ~25%
• Median survival untreated: 4 months treated: 12
months
Lung Cancer: SCLC
– Extensive
•
•
•
•
Beyond one hemithorax
Treated palliatively with chemotherapy
Median untreated survival 6 weeks
Median treated survival 9 months
Breast Cancer
• In many ways, treatment by stage is
similar to lung cancer:
– Stage I-II
• Limited to breast and axillary lymph nodes
• Surgery alone cures 40-90%
• Adjuvant chemotherapy or hormonal therapy
reduces relative risk of relapse by ~30%
• Adjuvant radiation reduces risk of local relapse
after breast-conserving surgery
Breast Cancer
• Stage III
– Locally advanced disease, often not
amenable to surgery initially
– Many respond to neoadjuvant chemotherapy,
and go on to surgery
• Stage IV
– Palliative, with hormones, chemotherapy,
monoclonal antibodies, radiation as indicated
– Median survival ~1.5 years, but lots of
variation
Colon Cancer
• Staged by CT abdo, chest X-ray, bone and
brain scan if rectal, rather than colon
• 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%
– Adjuvant chemo and radiation often used
together in rectal, rather than colon cancers
Colon Cancer
• Stage IV
– Palliated by chemotherapy, radiation as
indicated
– Untreated survival ~4-6 months
– Optimally treated survival ~24 months
Prostate Cancer
• Treatment determined in large part by
grade of tumour, and age of patient, in
addition to stage
• There is controversy about treatment at
virtually all stages of disease
• For cancer limited to the prostate, the
controversy is between radical radiation
and surgical resection
Prostate Cancer
• 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
Generic Treatment Algorithm for
Solid Tumours
• Localized cancer (Often stage I-II)
– Surgical resection with adjuvant chemo or
hormones as appropriate
• Locally Advanced Cancer (Often stage III)
– Combined chemo and radiation, with curative
intent
• Metastatic Cancer (Stage IV)
– Palliative chemo, hormones, + radiation