Oncology LMCC Refresher Course

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Oncology LMCC Refresher Course

• Dr. Garth Nicholas

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Outline

• How Big A Problem?
• Cells and Molecules
• Risk Factors and Screening
• Diagnosis and Staging
• Treatments
• Specific Cancers

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How Big A Problem?

• 145 500 new cancers in Canada in 2004
• 68 300 cancer deaths in 2004
• Projected to be the commonest cause of death in
  Canadians by 2010.

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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

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Canadian New Cases and Deaths
Tumour New Cases Deaths Case-Fatality Rate
Lung 19900 16900 0.85
Breast 19800 4900 0.25
Colon 16400 6560 0.40
Prostate 16100 2737 0.17
NHL 6800 2720 0.40
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Women
Men
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Women
Men
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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

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• Exceptions to the nomenclature rules
• Hepatoma
• Melanoma
• Leukemia
• Glioblastoma

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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

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Carcinomas

• Adenocarcinoma
• Breast
• Lung
• Prostate
• Most GI, including colon
• Endocrine malignancies
• Characterized by gland formation

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Carcinomas

• Squamous carcinoma
• Head and neck cancers
• Lung
• Skin
• Cervix
• Esophagus
• Anus

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Carcinomas

• Germ Cell Tumours
• Most commonly testicular cancers
• Ovarian
• Primary mediastinal
• Histologic subtypes include teratomas, embryonal
  carcinomas, yolk sac tumours

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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

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Sarcomas

• Known tissues of origin
• Liposarcoma Fat
• Rhabdomyosarcoma Striated muscle
• Leiomyosarcoma Smooth muscle
• Osteosarcoma Bone
• Chondrosarcoma Cartilage
• Unknown tissue of origin
• Malignant fibrous histiocytoma, Ewings Sarcoma,
  alveolar soft parts tumour

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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

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Blastomas

• Aggressive childhood tumours
• Neuroblastoma, retinoblastoma, medulloblastoma
• Named for their histologic resemblance to cells
  at the centre of blastocytes

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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

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Genetic Changes

• Cancers arise due to changes in a cells genetic
  machinery
• These changes involve genes that are divided into
  two major groups
• Oncogenes
• Tumour suppressor genes

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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

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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

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Genetic Changes

• CML is driven by the bcr-abl oncogene
  (Philadelphia chromosome)

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Genetic Changes
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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

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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

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Risk Factors
Factor Type Attributable Risk
Environmental 5
Lifestyle 45
Occupational 4
Pharmacologic 2
Biologic 4
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Risk Factors

• Environmental Causes
• Aflatoxin Hepatocellular carcinoma
• Erionite Mesothelioma
• Radon Lung (RR2)
• Solar Radiation Melanoma (RR3)

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Risk Factors

• Lifestyle Causes
• Tobacco Lung (RR12) 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

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Risk Factors

• Occupational (35 factors listed)
• Benzene Leukemia (RR3)
• Asbestos Mesothelioma (6), lung (3)
• Pharmacologic (18 factors listed)
• Alkylating agents (9) Leukemias
• Immunosuppressants(2) Lymphomas
• Hormones (5) Endometrium
• Others (2)

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Risk Factors

• Biologic Causes
• EBV Burkitts lymphoma (RR30)
• 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)

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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

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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

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Screening

• Lead-time Bias

Cancer becomes incurable
Symptoms
Cancer starts
Diagnosis and treatment
Death
Time
Treatment
Diagnosis by screening
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Screening

• Length Time Bias

1
2
3
4
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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

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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

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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 province-wide policy
• Other modalities are inconsistently used, and
  probably too expensive for mass screening

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Why Not Screen for All Cancers?

• Cancer-related factors

Cancer Starts
Symptoms
Death
Incurable
Preclinical interval too short
Incurable
Cancer Starts
Death
Symptoms
Cancer incurable, even if screen detected
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Why Not Screen for All Cancers?

• Test-related factors
• Test not sensitive/specific enough
• Test cant be applied to whole population
• Too expensive
• Insufficient infrastructure/personnel
• Unacceptable to majority of population
• Tumour not common enough

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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

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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

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Diagnosis

• Symptoms from regional (nodal) spread
• Lung (mediastinal nodes)
• SVCO, esophageal obstruction, hoarse voice, etc
• Breast (axillary nodes)
• Lump under arm

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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

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Diagnosis

• Paraneoplastic Syndromes
• Common, non-specific
• Poor appetite, weight loss, DVT
• Hormonal syndromes
• SIADH, Cushings, hypercalcemia, carcinoid
• Neurologic syndromes
• Lambert-Eaton Syndrome, demyelination syndromes

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Diagnosis

• Ultimately, diagnosis requires tissue
• Fine needle aspirate
• Core biopsy
• Excisional biopsy
• Open biopsy

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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

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Staging

• Most cancers are staged with a TNM staging
  system, which leads to overall stage I-IV
• Tumour
• Nodal
• Metastases

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Staging

• Breast Cancer

T1 1-20 mm T2 20-50 mm T3 gt50 mm T4 Chest wall,
skin, or inflammatory
N0 No Nodes N1 Mobile axillary nodes N2 Fixed
Axillary Nodes N3 Internal Mammery Nodes
M0 No distant metastases M1 Distant metastases
present
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Staging
T N M Stage 1 0 0 1 1 1 0
2A 2 0 0 2A 2 1 0 2B 3 0 0
2B 3 1 0 3A Any 2 0 3A 4 Any 0
3B Any 3 0 3B Any Any 1 4
Only people who work with cancer every day
actually memorize these.
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Staging

• Another staging system worth remembering is the
  Ann Arbour stages for Hodgkins disease

Stage Definition I Involvement of a single node
region II Two or more node regions on same side
of diaphragm III Lymph node regions on both
sides of the diaphragm IV Involvement of one or
more extranodal sites in addition to the site
for which the suffix E is used (see
below) Suffix A Absence of B
Symptoms B Presence of B Symptoms fever,
drenching night sweats, loss of gt10 body
weight in preceeding 6 months E Involvement of
single extranodal site contiguous with nodal
disease X Bulky disease (nodal mass gt10 cm,
or mediastinum widened gt1/3)
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Treatment

• Intent of Treatment
• Radical vs. Palliative
• Adjuvant
• Neoadjuvant
• Modalities of Treatment
• Surgery
• Radiotherapy
• Systemic therapy

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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

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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, Burkitts lymphoma

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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

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Treatment Radiation

• Ionizing radiation delivered to tumour and
  surrounding tissue
• Teletherapy
• 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

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Brachytherapy
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Teletherapy
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Treatment Radiotherapy

• Long-Term Complications
• Most related to long-term microvascular changes
• Radiation pneumonitis/pulmonary fibrosis
• Demyelination/memory changes/dementia
• Infertility
• Second cancers

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Treatment Systemic Therapy

• Chemotherapy
• Hormonal Therapy
• Immunotherapy
• Small molecules/monoclonal antibodies

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Treatment Chemotherapy

• Based on the (now disproved) notion that cancer
  cells divide more rapidly than normal cells
• Chemotherapy drugs tend to interfere with a
  cells ability to divide normally
• Cells which cannot divide normally should undergo
  apoptosis

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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

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Treatment Chemotherapy

• Acute toxicities
• Mucositis/diarrhea
• Nausea
• Hair loss
• Myelosuppression
• Risk of febrile neutropenia

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Treatment Chemotherapy

• Chronic Toxicities
• Infertility
• Particularly alkylating agents
• Leukemogenesis
• Anthracyclines, alkylating agents
• Neurotoxicity
• Cisplatin, taxanes, vinca alkyloids
• Nephrotoxicity
• Cisplatin

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Treatment Hormonal Therapy

• Hormone sensitive cancers
• Breast
• Prostate
• Endometrial
• Ovarian
• Tumours retain some characteristics of the
  original tissue

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Treatment Monoclonal Antibodies
Antibody Target Tumour Trastuzumab
(Herceptin) HER-2 Breast Rituximab
(Rituxan) CD-20 Lymphoma Cetuximab
(Erbitux) EGFR Colon Bevacizumab
(Avastin) VEGF Colon, Lung Tositumomab
(Bexxar) CD-20 I131 Lymphoma Ibritumomab
(Zevalin) CD20 Y Lymphoma
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Treatment Small Molecules

• Molecules developed to inhibit specific
  proteins/enzymes responsible for malignant
  behavior
• Imatinib (Glivec) CML, GIST
• Gefitinib (Iressa) Lung cancer
• Erlotinib (Tarceva) Lung cancer

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Lung Cancer

• Divided into
• Non-small cell 80
• Adenocarcinoma
• Bronchoalveolar carcinoma
• Squamous
• Large Cell
• Small cell 20

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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

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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 18
• Treatment can be difficult, and many patients are
  not candidates

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Lung Cancer NSCLC

• Stage IV
• Metastatic disease
• Incurable, with median untreated survivals of 4
  months
• With chemotherapy, median survival increases to 8
  months
• 50 of patients have improved symptoms or QoL on
  chemo

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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

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Lung Cancer SCLC

• Extensive
• Beyond one hemithorax
• Treated palliatively with chemotherapy
• Median untreated survival 6 weeks
• Median treated survival 9 months

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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

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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

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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

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Colon Cancer

• Stage IV
• Palliated by chemotherapy, radiation as indicated
• Untreated survival 4-6 months
• Optimally treated survival 24 months

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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

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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