Transcript Infection and sepsis - NUS Yong Loo Lin School of Medicine

Principles of Cancer Care
Introduction
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Overall cancer incidence rising
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Some cancers have reduced incidence
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breast, colon, lung, prostate,lymphoma
cervix, stomach, endometrial
Second highest cause of mortality
Principles of Cancer Care
Terminology
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Neoplasia - new growth
 malignant - uncontrolled growth and
dissemination
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Hyperplasia - increased cell number
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Metaplasia - mature cell type replacement
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Dysplasia - altered epithelial cell size, shape
and orientation. CIS most severe form
Principles of Cancer Care
Causes of Neoplasia
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Immunodefficiency - transplant tumours,
Kaposi
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Familial - Breast cancer, MEN, Lynch, FAP,
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Physical carcinogenesis
foreign body - asbestos
 ionizing radiation
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Chemical carcinogenesis
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Viruses
Biology of Cancer
Clonality
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Most tumours arise from a single
altered cell
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Most transformed cells die or are
destroyed
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Surviving cell
 heritability
 escape from normal control
Biology of Cancer
Tumour volume doubling
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Single cell - 30 doublings  1 cm3
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Lethal at 40 doublings - 1 kg
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Tumour growth is initially fast followed by growth deceleration
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Clinically doubling in tumour size
over 2-3 months
Tumour With Hypoxic Cells
Biology of Metastasis
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Tumour acquires blood supply even
before they are palpable  early
metastatic potential
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Cure of cancer must include
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attempt to eradicate primary completely
attempt to eradicate metastasis
Biology of Metastasis
Active or passive dissemination of
neoplastic disease from primary to
distant site
change enables cells to enter circulation
 adherence to endothelial walls
 extravasation
 invasion of stroma
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Biology of Metastasis
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Haematogenous spread
most tumour cell in bloodstream are rapidly
destroyed
 < 0.1% of cells survive to invade
 surviving cells are selected resistant
subpopulation of primary tumour
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Subpopulation characteristics for metastasis
destruction of basement membrane to enter vessel
 survival of blood turbulence
 appropriate ligand for cell adhesion molecule
 motility ability
 degradative enzymes - collengenase type IV
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Biology of Metastasis
Subpopulation characteristics for metastasis
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successful tumours can grow to 1-2 mm
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further growth requires acquisition of blood
supply
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angiogenesis is active process requiring
tumour angiogenic factors
Highly vascular tumours have increased potential
for metastasis - more likely that suitable cell will
eventually enter blood stream
Biology of Metastasis
Lymphatic spread
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Host invasion causes lymphatic vessel
penetration
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Tumour emboli may get trapped in first node
or bypass to more distant node - skip lesion
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Lymph nodes react to tumour and enlarge
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Are nodes a barrier/filter ?
Lymphatic /vascular anastomosis exist
 nodal enlargement is a marker for
dissemination
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Blood Supply of the Colon
Biology of Cancer
Mortality from cancer
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Local tumour effect
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Metastatic disease
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Systemic effects
malnutrition
 depression of immunocompetence
 cytolkine/other compound release
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Understanding each tumour natural history is
essential for therapy planning
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e.g. difference in breast Ca and head/neck Ca
Biology of Cancer
Mortality from cancer
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Local tumour effect
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Metastatic disease
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Systemic effects
malnutrition
 depression of immunocompetence
 cytolkine/other compound release
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Understanding each tumour natural history is
essential for therapy planning
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e.g. difference in breast Ca and head/neck
Ca
Importance of Early Detection
of Tumours
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Too early for mutation to cells that can
spread - eradicated before metastasis
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Treatment may reduce tumour bulk
enough for immune system to manage
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Too early to acquire resistance to
chemotherapy
Screening for Tumours
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High incidence population
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Population at risk
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Sensitive, cheap non invasive tests
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Hep B carriers - HCC
APC gene and FAP
racial - Japanese and stomach cancer
Familial breast cancer
pap smear, faecal occult blood, mammogram
Early stage of tumour - treatment makes a
difference
Screening for Tumours
Lead Time Bias
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diagnosis made earlier, prognosis not
made better
Length Bias
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slow growing tumours, longer
preclinical stage
Self Selection Bias
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persons who present themselves for
screening cf. The general population
Surgical Principles
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Diagnosis
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Staging
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Fitness for surgery / treatment
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Surgery and or other treatment
Surgical Principles
Methods of Diagnosis
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Fine needle aspiration
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Histology
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incision
excision
luminal
percutaneous wide bore needle
- guided by imaging
Tumour markers
Window for FNA
Luminal biopsy
Luminal biopsy
Laparoscopic Biopsy
Lap Biopsy of Liver Lesion
Surgical Principles
Staging - UICC normenclature
T -tumour
 N- nodal status
 M - metastasis
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The T,N,M is transcribed to a
stage group I, II, III, IV
Mucosa
Submucosa
Muscularis propria
Pericolic
perirectal
tissue
Subserosa
Serosa
Mucosa
Submucosa
Muscularis propria
Subserosa
Serosa
Surgical Principles
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Stage Groups
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I - early treatable
II - early treatable (nodes +ve)
III - locally advanced
IV - Metastatic
Stage I & II : early - curative approach
Stage III
: locally advanced - potential
for cure
Stage IV : systemic - palliation
Surgical Principles
Staging
Clinical
Imaging
Intraoperative
Pathological - pTMN
Surgical Principles
Fitness for surgery/treatment
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CVS, Renal, endocrine, Resp., haematopoetic
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Additional test if warranted e.g. 2D ECHO
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Specific situations  Liver - Childs grade
 Thorax - spirometry, blood gases
Major Treatment Modalities
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Surgery
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Ionising radiation - RT - Radiotherapy
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Chemotherapy
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Hormonal Therapy
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Immunotherapy
Principles of Surgical Oncology
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Radical surgery alone replaced by
multimodality approach
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Lymph node involvement
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Appreciation of early metastatic potential
Risk of tumour margins
Marker of metastatic disease - phenotype
capable of producing metastasis is present
Survival in node positive is disease is half
node negative disease
Malignancies don’t always spread stepwise
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primary  lymph nodes  distant sites
Principles of
Surgical Oncology
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Survival has improved with
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less radical surgery
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early detection
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treatment modalities for metastasis
Surgical Principles
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Surgeon must understand
natural history
 pattern of mets
 failure patterns
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Decision
aim of treatment - cure or palliation
 need for other modalities
 timing of different modalities
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Surgical Principles
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Surgery may be for
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primary disease eradication - radical operation
secondary eradication or debulking
palliation such as bypass, palliative resection
Radical operation
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removal of tumour completely
removal of wide margin of normal tissue
removal of primary draining lymphatics
obey oncological principles
Radical
Wipple operation
Operative specimen - Wipple Operation
Gastrojejunostomy for Palliation
Radiotherapy
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Ionizing radiation - photons and electrons
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higher energy ® deeper penetration
destroys important molecules e.g. DNA,
reaction with water produces free radicals
 damage of DNA and other molecules
unit of energy is the gray Gy = 100 rad
delivered by brachytherapy or teletherapy
In general for local control of neoplasm
Ionizing radiation
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Multiplying tumour cells are sensitive
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G0 tumour cells protected
• Cells at centre of solid tumour
• Ischemic cells
• Hypoxic cells
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Multiplying normal tissue at risk
• skin, GI mucosa, bone marrow, germ cells
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Quiescent normal tissue not sensitive
• Bone, liver
Tumour With Hypoxic Cells
RT- Increasing dose kills more tumour
cells as well as normal tissue
RT - Tumour destruction vs organ
complications - probability curves
Radiotherapy
Fractionation
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Total dose given in series of small doses
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Reduces damage to normal tissue
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Maximises tumour killing
Radiotherapy
Fractionation – how does it work ?
Each doses kills sensitive cells but spares
G0 cells
 Reoxygenation of remnant G0 cells makes
them divide and be susceptible tumour each fraction kills more cells
 Normal tissue is spared due to repair after
each small sublethal dose – minimise
complications
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Radiotherapy With Surgery
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Surgery removes tumour but margins are
at risk for seeding
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Wider surgery increases complications
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RT excellent for margins (oxygen rich)
poor for center of tumour (oxygen poor)
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Combination of surgery followed by RT
increases probability of free margins and
reduces local recurrence
Principles of Chemotherapy
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Tumour mass growth slows as tumour
enlarges - cells at center die or remain
dormant (G0) because of blood supply
limitation
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Only dividing cells (growth fraction) are
killed
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Growth fraction is maximum at 37% of
max size
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Each dose of chemotherapy kills a fraction
of total cells
Principles of Chemotherapy
Concept of log kill
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Suppose a patient has 10 mets of 1 cm3 each
(109 cells) – total of 1010 cells.
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One cycle of drugs produces 1-log kill or
90% eradication
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6 drug cycles will give 6-log kill or
99.9999% eradication
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Each met will then have 103 cells left clinically undetectable(complete remission)
– but recurrence is likely
Principles of Chemotherapy
Concept of log kill
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If we start with smaller volume after 6
drug cycles we may have 102 cells per met
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Immune system may be able to mop up actual cure
Principles of Chemotherapy
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Chemotherapy for solid tumours is most
effective for small (early) tumours
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Not suitable for solid primaries
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Ideal for early metastasis
In general ChemoRx is for systemic
control after primary treatment
Types of Chemotherapy
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Curative - for tumours with 100% growth
fraction - blood malignancies
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Adjuvant - treatment of micrometastasis
after curative treatment of primary by other
modality usually surgery
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Neoadjuvant - given before definitive
surgery
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Palliative - “control” of disseminated disease
Administering Chemotherapy
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Select effective drug - consider toxicity
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Calculate dose needed - consider patient
performance, co morbid conditions
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Suitable intervals to allow normal tissue
to recover - esp. bone marrow
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Support patient and treat toxicity
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Compassion & Quality of Life
Administering Chemotherapy
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Plant Alkaloids
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Antibiotics
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Alkylating Agents
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Antimetabolites
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Combination Chemotherapy
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prevents emergence of early resistance
additively increase in cytotoxic potency
Cancer Therapy
Nutritional Care
Hospice Care
Pain Management