Oncology Revision

Paul Baillie

Go to slide 96
 Environmental Factors
• Cancer is a multifactorial disease!
– Genetic, viral, Diet and Chemical Inputs!

• VIRAL
– EBV 
Burketts lymphoma (children) &
Nasopharyngeal Carcinoma &
Hodgkin’s Lymphoma
– HPV 
Cervical Ca
NB there is a vaccine to HPV 16 & 18
– HBV / HCV 
80% of Hepatocellular Carcinoma
– HTLV 
Adult T cell lymphoma (a highly aggressive Non-Hogkins) and
leukaemia
(HTLV = Human T cell lymphoma virus)
– HIV 
Kaposi’s Saroma (HHV8) / pleural effusion lymphoma / Testicular Ca
 Environmental Factors
• Bacterial
– Gastric Adenocarcinoma and gastric
lymphoma is associated with…
Helicobacter Pylori

• Parasites
– Schistosomiasis Haematobium is associated
with…
bladder cancer (in the developing world)
 Environmental Factors
• Diet
– High intake of fruit and veg is inversely proportional to some
cancers…
• Laryngeal, Lung & GI tract
– High meat intake increases the risk of GI ca.
– Obesity in adults is a critical risk factor for
• Endometrial Cancer and increases the risk of
• Breast Ca (postmenopausal) & Kidney Ca
– Salt Fish is associated with
• Nasopharyngeal Ca associated with HLA BSIN2

Having median daily intake of aphlatoxins (produced by

aspergillus species of mould) may reduce the risk of
hepatocellular carcinoma
 Environmental Factors
• Alcohol
– Alcohol is associated with what cancers?

• Head and Neck

• Oesophageal
– Especially squamous

– Alcholic Cirrhosis is a risk factor for Hepatocellular

Carcinoma

– Alcohol has an additive effect with tobacco in causing

cancer. True or False?
FALSE – it has a synergistic effect- tres bad!
 Environmental Factors
• Smoking
– Smoking is the single largest avoidable cause of
premature death and the most important known
carcinogen.
– Associated with…
> 90% of Lung Cancer
Bladder Ca
Oesophageal Ca
Head and Neck Ca
– 15% of ca worldwide and >30% of cancer in men in
the developed world is associated with smoking
– Has a synergistic effect on cancer caused by other
carcinogens e.g. Aspestos
 OCP
• Increases the risk of
– Breast Ca
– Cervical

• Decreases the risk of

– Ovarian Ca
 Most Common Cancers
Men Women

1. Prostate 1. Breast
2. Lung 2. Colorectal
3. Colorectal 3. Lung
 Cancer Screening
• Prerequisites...
1. Important public health issue
2. Understand natural hx of disease
 determines age of screened population
3. Recognisable at an early stage
4. Early treatment – beneficial
5. Suitable test available
6. Test is acceptable
7. Adequate facilities for diagnosis & rx
8. Determine if repeat sceening needed
9. Benefits should outweigh risks
10. Should be cost effective
 Important public health issue
Understand natural hx of disease
Early stage forms of Ca Recognisable at an early stage
Early treatment – beneficial
Suitable test available
Test is acceptable
Adequate facilities for diagnosis & rx

• Cervix:
Determine if repeat scening needed
Benefits should outweigh risks
Should be cost effective

– Cervical Intraepithelial Neoplasia (CIN)

• Breast:
– Ductal Carcinoma in Situ (DCIS)

• Colorectal:
– Adenomatous Polyps

• Prostate:
– Carcinoma In Situ
– Prostate Interstitial Neoplasia
 Important public health issue
Understand natural hx of disease
Recognisable at an early stage
Early treatment – beneficial
Suitable test available
Test is acceptable
Adequate facilities for diagnosis & rx

• Sensitivity Determine if repeat scening needed

Benefits should outweigh risks
Should be cost effective

– The proportion of people testing positive of those who

have the disease
– Greater sensitivity = fewer…
false negatives

• Specificity
– The proportion of people testing negative of those
who do not have the disease
– Greater Specificity = fewer…
false positive

NB: CEA is positive in bowel cancer but also many other things!
 Important public health issue
Understand natural hx of disease
Recognisable at an early stage
Early treatment – beneficial
Suitable test available
Test is acceptable
Adequate facilities for diagnosis & rx
Determine if repeat scening needed
Benefits should outweigh risks
Should be cost effective
Take-UP Rates

– Cervical Smear = 80%

• Those most likely to benefit do not take it up:

– Best uptake in women > 60 years
– Worst in Afrocarribeans who tend to have aggressive ca

– Mammography = 75%

– FOB =60%
 Important public health issue
• Cervical Screening Understand natural hx of disease
Recognisable at an early stage
Early treatment – beneficial
– 3 yearly 25-49 Suitable test available

– 5 yearly 50 years to 64 Test is acceptable

Adequate facilities for diagnosis & rx
Determine if repeat screening needed
Benefits should outweigh risks
Should be cost effective

• Breast screening
– 3 yearly 50-70
– Then voluntary
– Under 50 - MRI in at risk women

• Colorectal
– ?60-70 yearly or 2 yearly
– Started April 2006 and being rolled out across the country
– Fully rolled out y 2009
– FOB sample posted. Result in 48 hrs
– Follow-up Colonoscopy

• Interestingly there are specific policies not to screen

– Prostate Ca – EL(97)12
– Neuroblastoma
 Important public health issue
Understand natural hx of disease
Recognisable at an early stage
Early treatment – beneficial
Suitable test available

Negative Aspects of Screening Test is acceptable

Adequate facilities for diagnosis & rx
Determine if repeat screening needed

– False Negatives Benefits should outweigh risks

Should be cost effective

• Give false hope

– False Positives
• Cause stress
– Detection of low grade tumours
• Unlikely to progress in older age group
– Complications of tests
• Mammography
– radiation
• Colonoscopy (following +ive FOB)
– perforation
 Important public health issue
Understand natural hx of disease
Recognisable at an early stage
Early treatment – beneficial
Suitable test available
Test is acceptable
Adequate facilities for diagnosis & rx
Determine if repeat sceening needed
Benefits should outweigh risks

• Cost per life

Should be cost effective

– Cervical 30k

– Breast 54k

– Colorectal 42k

• NB Breast ca is probably a waste of time, as since screening started

treatment has improved so much so that generally invasive ca can
be cured.
 Recent Advances in Screening
• Cervical
– Liquid Based Cytology
• Reduces inadequate tests from 9% to 1%
• Fewer women recalled
• Quicker reporting time
– HPV testing
• Hybrid Capture HPV test

• Breast
– Two View Mammography
• Cranio-caudal & Medio-lateral Oblique
• Increases detection rate by >25% up to 89% accuracy
– MRI screening for women at risk under 50
• Based on family hx
• Mammograms aren’t v good at detecting breast ca in
premenopausal women due to higher breast density
 Tumour Makers
• A ‘tumour marker’ is…
– Any substance which can be related to the presence or the progress of
a tumour

• It can be “tumour specific” (only produced by tumour tissue) or

produced in relatively larger amounts in malignant cells cf. non-
malignant cells (usual scenario)

• Normal levels do NOT exclude neoplasm

• Different methods are NOT always comparable

– Follow-up by different lab can be mis-leading

• “Shotgun” requesting will cause lots of unexplained results

 Perfect TM
(Doesn’t exist)
• 100% specific (no false positives)
• 100% sensitive (no false negatives)
• Close correlation between blood TM concentration and
the tumour size

TM Uses
• Screening - limited by lack of sensitivity and specificity
• Prognosis – Some markers help predict outcome
• Detecting relapse, response to therapy
– Biggest use!!!
 Types of Tumour Markers
• Structural molecules- carbohydrate
antigens
– CEA, CA19-9, Ca15-3, CA 125

• Secretion products, enzymes, hormones:

– AFP, hCG, PSA, catecholamines

• Cell turnover markers

– Hypercalcaemia, erythrocytosis, anaemia
 Classical Tumour Use
• Myeloma
– Paraprotein band
• Bence Jones – Ig light chains

• Phaeochromocytoma
– Urine and serum catecholamines

• Carcinoid
– 5HIAA (Urine)
– Chromogranin A (plasma)
• NB: A carcinoid tumour is a neuro-endocrine tumour. Carcinoid Syndrome due to kallikrein and serotonin
histamine release  flushing, diarrhoea & abdominal cramps.
Diagnosis: Plasma levels of Chromogranin A + clinical suspicion (may be supported by urinary 5HIAA)
• Ca 19-9 Routine TMs
– Pancreatic Ca
• Chromogranin A
– Carcinoid
• Ca 15-3
– Breast Ca
• Ca 125
– Ovarian Ca
• PSA (Prostate Specific Antigen)
– Prostate Ca
• AFP (Alpha Fetoprotein)
– Testicular Ca (Non Seminomatous Germ Cell) (MONITORING)
– Hepatocellular
• HCG (Human Chorionic Gonadotrophin)
– Testicular / Ovarian ca (MONITORING)
• CEA
– Colorectal Ca (MONITORING)
• LDH
– Non-Hodgkin’s Lymphoma (MONITORING)
• Urinary 5HIAA
– Carcinoid
• Calcitonin
– Medullary Thyroid Ca
 Same Slide testing in another way
Name the best tumour marker for these…
• Ovarian Ca?
– Ca 125
• Testicular Ca?
– APF & HCG
• Breast?
– Ca 15-3
• Colon?
– CEA
• Pancreas?
– Ca 19-9
• Carcinoid?
– 5HIAA & Chromogranin A
• NHL?
– LDH
 PSA
• Not diagnostic!
– Main use is monitoring treatment / reoccurance
• <4ug/L in health, but 30% of patient with organ confined
ca also have those levels
• Test improvements:
– Age related reference ranges, doubling time and free/bound
PSA
• Also increased in
– BPH
– Prostate Ischaemia
– Urinary Retention
– Acute Renal Failure
– Rectal Examination
 CEA
Carcinoembryonic Antigen
• We don’t know its biological function
• Rising CEA can preceed clincally recognisable
cancer by 46 months!!!

• Elevated in
– Colorectal Ca
– Melanoma, Lymphoma, Breast, Lung, Pancreas,
Stomach, Bladder
– Smoking
– IBD
– Liver disease
 AFP
Alpha-foeto Protein
• Normally produced by developing foetus
• Used classically in Testicular Ca
• Elevated in
– Testicular Ca
– HCC
– Germ Cell Ca (Ovary or testes)
– Hapatoblastoma
– Liver disease
– Pregnancy
– First year of life
 Ca 125
• Classically used in Ovarian Cancer
• Also raised in…
– Ca of the Uterus, Cerivix, Pancreas, liver or intestine
– Liver dx
– Pancreatitis
– Any condition causing inflammation of the pleura
– Menstruation
– Pregnancy
 Ca 19-9
• Classically used in Pancreatic Ca
– Higher levels associated with advanced dx
– Unfortunately pancreatic ca is basically so severe it’s untreatable
• Originally discovered in colorectal ca and also raised in
hepatobiliary dx.

Ca 15-3
• Classically seen in breast ca
• Rarely raised in early dx
• Can also be elevated in benign breast or ovarian dx
 The cell cycle
• The most important checkpoint in the cell
cycle is between G1 and S.
– Cell size, Growth factor availability, Metabolic
State and DNA damage are all checked
before the cell goes into S1
– It is regulated by many growth factors and
genes including p53 (“guardian of the
genome”)
• Oncogenes
– Tyrosine Kinase Receptors
• HER-2
– Non-Receptor Tyrosine Kinases
• Src - Melanoma
– Ras
– Raf
– Mek
– Erk
– Chormosomal Abnormalities
• ABL-BRC
• IGH – cMyc gene is under control of IGH (Burkitts) 8;14

• Tumour Suppressor
– P53 (g1/s phase)
– pRB – retinoblastomas
– BRAC1 & BRAC2
– APC - binds betacatanin - colon (FAP)
– Mismatch repair genes (HNPCC) – MSH2,6 + MLH1, PMS1&2
 Oncogenes and Tumour
Suppressor Genes
• Tumour Suppressor genes
– Function becomes lost or inactivated in carcinogenesis
– Both copies must be inactivated before the tumour suppressor
function is completely lost i.e. behave in a recessive fashion
– Normal function – cell cycle control

• Oncogenes
– Function become enhanced in cancers
– They generally behave in a dominant fashion
– Proto-oncogenes are the non-mutated forms of these genes,
which normally play an essential role in controlling cell
proliferation
– They encode growth factors, GF receptors, signal transducers
and transcription factors
 Identification of Oncogenes
1. Transfer of fragmented DNA from cancer cells –
confers certain aspects of cancer phentype to
fibroblasts - allows isolation of the gene responsible
e.g. Ras
2. Found adjacent to sites of provirus insertion
e.g. C-myc as site of avian leukosis virus in bursal lymphomas
3. Viral oncogenes in acutely transforming retroviruses
found to be homologous to cellular oncogenes
src, ras, myc
4. Found adjacent to or spanning, breakage points of chr
translocations
e.g. c-myc, bcr-abl
5. Post-genomic technologies: DNA microassays,
sequencing cancer genomes
e.g. B-RAF
Identification of Tumour Suppressor
Genes
• Cell Fusion
 Loss of tumourigenicity as tumour phenotype is
recessive to normal

• Evidence from retinoblastomas

– Children that don’t inherit the Rb mutation, generally
have unilateral.
– A parent with the mutation will pass on the mutation
to 50% of their children
– This mutation causes a susceptibility to
retinoblastomas (the other allele need to be damaged
to produce malignancy)
– Generally this causes Bilateral cancer
 Signal Transduction
• Growth Factors
– Binding is specific and high affinity and induces a conformational
change
– Activates intracellular signalling

• Types of Receptor
– Polypeptide
• E.g. PDGF, EGF. Have intrinsic tyrosine kinase activity, become
phophorylated and link to effectors
• NB split proteins are involved in angiogenesis and are useful targets
– Peptide
• E.g LPA, Bombesin. 7 trans membrane domains couple via
heterotrimeric GTP binding proteins to receptors.
– Cytokines, growth factors
• E.g TNFα, CD40. Receptors couple to specific signal transducers
such as Src (a non-receptor Tyrosine Kinase) present in
melanomas.

• NB – cells have approx 100x more phosphatase activity than

kinase activity to protect it from being “on” all the time.
 Signal Transduction
RAS Signalling
• RAS is an oncogene
• There are many growth factors and their receptors that
activate RAS
• “ Ras  Raf  MEK  E R K  MAPK” sequence
– ERK activates transcription factors
• 3 forms: Ki, Ha, N
• Intrinsic GTPase
• Adaptor Protein
• Regulated by exchange factor and GTPase activity
protein
• Point Mutation of Ras in 50% of human tumours
– Mutation at codons 12, 13 or 61 reduce GTPase activity
– 90% of Pancreatic Carcinomas, 50% Colon and lung have K-
RAS mutations, N-RAS mutation in myeloid
• B-Raf mutation in 60% melanomas
 Signal Transduction
Src pathway
– Activity increased in >50% cancers from colon, liver, lung, breast
and pancreas
– EGFR activation stimulates the pathway
NB EGFR also activates the RAS pathway
– “Src-FAK-Abl-PDK-mTOR”
Sarcastic – f*ink – able PDK mTOR
– There are theraputic agents that work at various points on this
pathway
E.g. Erlotinib inhibits EGFR
- Used in NSCLC & pancreatic ca
Gleevec – ABL-specific TK inhibitor
- used in CML
Gefitinib / Iressa is a small-molecule inhibitor
of the EGFR tyrosine kinase
- Used in advanced NSCLC
 Signal Transduction
PI-3-Kinase Signalling
• PI-3 is one of the targets of RAS
• PI-3 activates PKB which causes proliferation of
the cell
• PTEN is the most commonly mutated gene in
human cancer
• PIK3CA gene is mutated in 32% of colorectal
cancers, 35% liver, 25% breast, 20%
glioblastomas …
 Signal Transduction
Cyclins, CDKs and Check Point Kinases
• Cyclin D is low in quiescent cells due to its
instability
• Growth factor-activated signalling causes
accumulation of cycD
• cycD/cdk4 phosphorylates Rb thereby releasing
E2F
• E2F initiates S-phase

• Topoisomerase Inhibitors such as irinotecan,

topotecan and etoposide
 Chromosomal Translocations
• Translocation of c-Myc on chromosome 8,
leading to accumulation of c-myc is a
hallmark of Burkitt’s lymphoma

• The philidelphia chromosome t(9;22) in

Chronic Myeloid Leukemia (CML) leads to
the expression of a chimeric BCR-ABL
fusion gene
Rx: Gleevec – alb-specific tyrosine kinase inhibitor
 Function of Rb
(Retinoblastoma Protein)
• Tumour Suppressor Gene
• pRB is involved in the regulation of the cell
cycle
• Once there is enough Cyclin D pRB gets
phosphorylated and binds EF2
transcription factor and prevents
transcription of target genes.
 p53
• Tumour Suppressor Gene
• Most common change in cancer
• Wide range of point mutations or loss
• Not essential for growth and development BUT
prevents DNA damage
• Causes initiation appropriate response (cell
cycle arrest, repair or apoptosis)
• Li-Fraumeni Syndrome – Germ-line mutations of
p53  Great susceptibility (AsBs) to breast ca,
brain ca, acute leukaemia , bone sarcoma &
adrenal cortical carcinoma
 Other Tumour Suppressor Genes
• BRCA1/2
– PARP inhibition leads to selective killing of BRCA1/2 tumour
cells

• ATM (Ataxia Telangiectasia Mutation Gene)

• Mismatch repair genes mutations

– Also called Microsatalite Instability (MI)
– Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

Note on FAP
APC (adenomatous polyposis coli gene) is responsible for hereditary FAP
(Familial Adenomatous Polyposis)
APC is involved in controlling cell proliferation
Mutated in 60 -80 % of sporadic colon cancers
 Epigenetic Changes
• Epigenetic changes are where Tumour
Suppressor Genes can be inactivated by
alteration of gene expression without
change in the DNA sequence

• E.g.
Methylation of the gene promoter
Gene Normal Function Associated Cancers
Tumour
Suppressor Gene
p53 Regulates transcription Breast, Lung, Colon,
a)
at the G1-S checkpoint glioma, sarcoma

Rb Cell cycle control Retinoblastoma,

b)
Small cell lung cancer
Osteosarcoma
MTS1 Cell cycle control c)
Glioma, melanoma, lung,
bladder, mesothelioma

BRCA 1 & 2 Transcription factors d)

Familial Breast and
Ovarian Cancer

Oncogenes
Ras Signal Transduction e)
Pancreas, Colon, Lung
Myc Transcription Factor f)Lung, breast, Cervix
Erb-B / HER-2 Growth factor receptor g)
Breast, Lung, Stomach
Src Signal Transduction h)
Colon, Melanoma
 A note on P-glycoprotein
• P-glycoprotein is on the BBB. It prevents
stuff getting into the CSF that shouldn’t get
in.
• Tumour cells sometimes express P-
glycoprotein on their cells to give them
immunity from theraputic agents.
 Systemic cancer therapy
• Includes.
– Cytotoxic Agents
– Immunomodulation
– Targeted Treatments
– Hormone Therapies
– New age biological therapies
 Radiotherapy
• History
– Roentgen &Beceuel
– Early use - only skin tumours
– Now brachytherapy for cervix & prostate

• Effects of radiotherapy
– Early  on rapidly turnover tissues
• E.g. mucous membranes, bone marrow, hair follicles
– Late  on slow turnover tissue
• E.g. glial tissues, vascular endothelium, lung, kidney
– Carcinogenesis
- RR 2.32 in Hodgkins + Radiotherapy
- RR 3.34 in NHL
- RR 27.48 in Leukaemia
• Radiobiology – 4 R’s
– Repair
– Reoxygenation
– Reassortment
– Repopulation

• Factors affecting tumour growth

– Mitogenic rate of clonogens
– Proportion of cells dividing
– Cell loss rate inversely proportional to volume
 Norton Simon Hypothesis
• Gompertiaz growth kinetics work both
ways:
– As tumours grow, the growth rate decreases
– As tumour shrinks growth rate increases
 Effects of Radiation
• Oxygen is required shortly after irradiation
for formation of oxygen radicals to
damage the tumour
• Oxygen Enhancement Ratio (OER)
– More cells kills in presence of oxygen than
without it
– Hypoxia-Inducible factor 1 (HIF1)
• Regulated cell response to hypoxia
• Itself is regulated by P53, IP3 etc. (oncogenes &
tumour suppressor genes)
 RT Planning
• Aims:
– Immobilise in optimum position
• E.g. Beam directional shell / orfit / vacubag
– Ensure reproducibility
• laser alignment
– Mark up of volumes – clinical or on CT
• See next slide
• Imaging
– conventional / CT / Fusion (Fusion is…P.ET +CT)
– Verification of treatment
• E.g. Portal Imaging
 RT Planning
• Target Drawing
– Most important step in planning RT
is defining the target

– Gross Tissue Volume

• As visualised clinically or on CT
– Clinical Target Volume
• Surrounding tissues might have
microscopic invasion
– Planning Target Volume Multileaf Collimeters use
• Allows for uncertainties in rx set- 0.5cm leaves to shape the
up: beam so RT is more focused
– Variations in pt positioning
It is also critical to define the
– Internal Organ Movement position of critical organs
– Tolerances of machine calibration - Kidneys, Spinal Cord, Eyes
 Intensity Modulated Radiotherapy
(Dynamic RT)
• With standard techniques it can be difficult to
treat an irregularly shaped target in close
proximity to a critical organ
• This may be improved by using intesity
modulated RT where the machine rotates
around the patient, continuously emitting X-rays
• Alternatively the intensity of radiation from each
beam may be modulated by moving the Multileaf
Collimeter during the treatment of each field
• The two techniques can be combined
 X-rays
• Electrons are accelerated by a potential difference
(voltage) across a vacuum
• When the e- hit a target, Xrays are produced

Physical Basis of RT
• Radiotherapy dose is measure in energy
deposited per unit mass = j/Kg = Gray
• Actual energy deposited is very little – the heat
produced by a typical treatment is <0.01˚C
• Effect on tissue is via DNA damage
 Clinical Delivery of Radiotherapy
• Generally given as a series of daily treatments called
fractions
• Typical schedules
– Radical
• 66 Gy/ 33fractions / 6.5 weeks
– Palliative
• 8 Gy / 1 fraction
• RT machines
– 100kV  Basel Cell Carcinoma Rx
• (esp. when on eyelashes)
– 250kV  Rib Metastases Rx
– 5MV
• Most common radiotherapy dose/ frequency for most tumours
• NB: Skin Sparing: Dose at skin is less than slightly further in
 New Fractionation Regimes
• Hyperfractionation
– More fractions / day
– Lower doses (<2Gy)
– Treatment duration constant
• Accelerated Fractionation
– Fraction number constant
– Multiple daily fractions
– Shorter Duration
• Can combine both
– the CHART regime (Combined Hyperfractionation Accelerated
RadioTherapy) in non-small cell lung cancer.
– This is used as there is evidence some cancers have the
capacity for rapid proliferation during a conventional 6 week
course of radiotherapy
 Radical Radiotherapy
• The highest tolerable dose usually given to maximise
eradication of cancer
• Lower doses for radiosensitive malignancies and to
eradicate microscopic residual disease of moderate
radiosensitivity.
• Considerable acute toxicity acceptable because of
anticipated survival benefit
 Clinical Uses of RT
The major use of RT in treatment is Adjuvant
Treatment

– Early breast ca -Medulloblastoma

– Sarcoma -Small Cell Lung
– Endometrial -“Involved
– Testicular Tumours Margins”
– Rectal - Thyroid (I131)
– ALL
- CNS
 Clinical Uses of RT
Brachytherpy
Needle insertion of radioactive seeds under GA

Uses
- Cervix
- Prostate
- Oesophagus (upper 1/3rd)
- Head and Neck
 Clinical Uses of RT
• Palliation • Neoadjuvant RT
– Pain – Rectal Cancer
– Head and Neck
– Bleeding
• Lung;
bladder; • Uses in Benign Dx
cervix; skin – Keloids (overgrown scars)
– Dysphagia – A/V Malformations
– Neurological – Acoustic Neuromas
Symptoms – Pituitary Adenomas
• Brain / spinal cord – Cardiac Brachytherapy
– SVCO – stents
– Thyrotoxicosis
 Combination Therapy
• The Goldie-Coldman Model…
“Cells mutate spontaneously to resistant
phenotypes”
– shows why combination therapy is better than rx
given sequentially
• If 2 non-cross tolerant treatment modalities are used, the
chance of simultaneous resistance to both drugs are greatly
reduced
– Show why adjuvant therapy is good
• Explains inverse proportion between tumour mass and cure
probablility
 Limits of RT as a treatment
• Volume of therapy is limited by normal
tissue tolerance
• Disease outside treated volume will not be
treated
• Some tumours as not sufficiently
radiosensitive to be eradicated by safe RT
doses e.g. glioblastomas
• Normal tissue tolerance precludes radical
treatment for local reoccurance
 The Future - Protons
• Protons have a
“bragg peak” which
means proton machines
give less of a dose of RT
in superficial tissue cf.
Megavoltage machines
 More Skin sparing
• Can aim the peak
radiation dose at the
tumour
• There are no proton
machines in the UK atm
but there are plans to
build one
 First line chemo intent in cancers
• Most germ line cancers and childhood cancers the intent
of chemo is
- Curative

• In Pancreatic Ca, Renal Ca, Hepatocellular carcinoma,

Cholangiocarcinoma, astrocytoma and malignant
melanoma the intension of chemo is
- Palliation
(little or no gain in survival)

• In most other cancers, the aim of 1st line chemo is

Prolongation of Survival
Cytotoxic Agents and the Cell
Cycle
 A note on Topoisomerase
• Topoisomerases regulate topological state of
cellular DNA
– Reduce DNA twisting and super-coiling
– Permit access to DNA for replication, repair and RNA
synthesis by cleaving and resealing the
phosphodiester backbone of DNA. Hold open strands
to permit passage of another ss or ds DNA.
• Topoisomerase Inhibition
– DNA replication results in irreversible dsDNA break,
G2 arrest and apoptosis in S phase
– Camptothetic analogues (e.g.Irinotecan used in CRC)
– Anthracyclins (e.g. Epirubicin used in breast ca)
 Chemo Terminology
Chemo Clinical Contexts:
• For advanced disease
– Where no other treatment exists; may be radical or palliative
• Adjuvant Chemotherpapy
– Systemic treatment, following local radiotherapy or surgery, to control
micrometastases
• Primary or neo-adjuvant chemotherapy
– Chemotherapy asinitial therapy for locally advanced cancer, to render it more
amenable to subsequent surgery improve cosmesis / function and to control
micrometastases.

Response to Chemotherapy
• Complete Response = …
– Prerequisite for not sufficient for cure. Implies improved survival
• Partial Response = …
– Palliative value only, offset by drug toxicity. More modest impact on survival.
• Stable Response = …
– Any impact on survival limited to continuous non-toxic therapy.
 Quality of Response from Chemo
may be defined by…
• Performance Status
– KARNOFSKI performance status
• 0-100 QoL index
• 100% - normal, no complaints, no signs of disease
• 0% - death.
– WHO / ECOG / Zubrod Performance Stat
• 0 – Asymptomatic
• 5 - Death

• Quality of Life Measurements

• Relapse-free survival, from time all treatment

discontinued
 Quality of Response from Chemo
may be defined by…
RECIST criteria (Response Criteria in Solid Tumours)
• Complete response – disappearance of all
known disease
• Partial Response – 50% or more decrease in
total tumour load
• No change – 50% decrease or 25% increase not
established
• Disease Progression – 25% or more increase in
measurable lesions or new lesions
 Chemotherapy Toxicity
• Low therapeutic index

• Careful dose calculation body weight,

body surface area or derived from renal
function.
NB

• Individual dose adjustment based on prior

dose toxicity
Common Chemotherapy Toxicities
Effects on diving cells Other Effects
• Myelosupression • Neurological
 Commonest dose limiting – Platinum agents & Taxanes
side effect • Nausea & Vomiting (bodies
• Mucositis protective mechanism)
– Mouth Ulcers, Diarrhoea… • Fatigue
– Secondary Infection • Cardiac
– Common with 5 Flourouracil
(CMF) – Anthracyclins eg. Epirubicin
• Toxic limiting factor with • Renal
5FU is mucositis – Platinum Agents (eg. Cisplatin)
Rx: Analgesia, Mouthwash • Pulmonary
Systemic + Topical Antifungal – Bleomycin  Fibrosis
Slow gut transit - loperamide
• Allergy
• Alopecia
• Skin
– red dry hands and feet
 Nausea and Vomiting
• Metaclopramide (D2 receptor & 5-HT3 antagonist)
• Domperidone (D2 & D3 receptor antagonist)
• Ondansetron / Granisetron (5HT3 antiagonists)
• High Dose Steroids e.g. Dexamethasone
– Dampens CTZ
• Aprepitant (NK1 inhibitor)

• IV rehydration if uncontrolled – esp. with

nephrotoxic agents like cisplatin
 Myelosuppression
• White cells, neutrophils  Lower resistance to infection
• Platelets  bruising / bleeding
• Red cells  anaemia

• Recovers
• May require blood product support or
replacement of function (anti-infective agents)
• GCSF (granulocyte colony stimulating factor)
can reduce severity and duration of neutropenia
Common Drug Regimes
 E-CMF
• Breast Cancer

• Epirubicin
 Reversible heart damage

• Cyclophosphamide
• Methotrexate
• Fluorouracil
 R-CHOP
• Non-Hodgkin’s Lymphomas

• Rituximab
– Monoclonal Anti-CD20

• Cyclophosphamide

• Hydroxydaunorubicin
• Vincrisitne
• Prednisilone
 ABVD
• Hodgkin’s lymphoma

• Doxorubicin (adriamycin)
• Bleomycin
• Vincristine
• Dacarbazine
 BEP
• Ovarian Cancer & Testicular

• Bleomycin
• Etoposide
• Cisplatin (contain Platinum)
 MIC
• Lung

• Mitomycin
• Ifosfamide
• Cisplatin
 Monoclonal Antibodies
Type Application Mechanism

Bevacizumab CRC, ?NSCLL, ?Breast Ca Anti-VEGF

Gemtuzumab Relapsed AML targets an antigen on

leukemia cell
alemtuzumab B cell leukaemia CD52

rituximab Non-hodgkinn’s lymphoma CD20

Trastuzumab Her-2 +ive Breast Ca erbB2 (HER2)

(HERCEPTIN)

erlotinib NSCLC (2nd line), Pancreatic Ca HER-1 / αEGFR

Imatinib CML ATP receptor on BRC-

ABL tyrosine kinase
nimotuzumab SCCHN, Glioma EGFR
 Endocrine Therapy
• Used in
– Breast Ca
– Prostate Ca
– Carcinoid Tumours
– Endometrial Ca
– Ovarian Ca
 Hormone Therapy Approaches
• Antioestrogens
– Tamoxifen, Raloxifen, Fulvestrant
 Breast Ca
• Antiandrogens
– Flutamide, Casodex
 Prostate Ca
• GnRH (Gonadotrophin Releasing Hormone) “agonists” = LHRH agonist
– Goserelin (Zoladex), Leuprorelin
 Breast and Prostate Ca
• Long acting analogues of negative regulators
– Somatostatin Analogues e.g. Octreotide
 Carcinoid Tumours
 Aromatase Inhibitors
• Irreversible – examestane
• Reversible – anastrazole

• Aromatase converts androgens to

oestrogens
 Treatment of Pain
• Visceral 
Opioids
• Bone 
NSAIDs
• Neuropathic 
Gabapentin, Amitryptillin

Analgesic Ladder
– Step 1 =
Paracetamol / NSAIDs
– Step 2 =
Weak Opioid e.g. Codeine, Tramadol
– Step 3 =
Strong Opioid e.g. Diamorphine, Fentanyl, Oxycodone
 Prescribing Opioids
• When prescribing a slow release opioid (such as MST or
Zomorph) the prescription has to be (and have)…
– Handwritten
– Need to of opioid needed
• E.g. MST continuous 40mg b.d. for 7 days. Total 14 (fourteen) 30mg
tablets + 14 (fourteen 10mg tablets)
• You also need put the total quantity to prescribe
– An immediate release opioid for “breakthrough pain”
• PRN dose is 1/6th of total opioid dose (e.g. Oromorph, Sevredol)
– An antiemetic
• E.g. cyclizine 150mg
• Nausea and vomiting occur in the first week of opioid use
– A laxative
• For the constipation (SE)

• Syringe Drivers
• Deliver s/c medications (often several drugs combined) over 24hrs
• S/C morphine is 2x as potent as oral
 Recognising A Dying Patient
The Liverpool Care Pathway
– Change in conscious level
– Peripherally shut down
– Taking only sips of water
– Bed bound
– Unable to take oral medications

Gold Standards Framework

– In primary care there is a register of patients who are thought to have 6
months or less to live.
– These patients have more services open to them

Verification of Death
– Fixed and Dilated Pupils
– No heart sounds
– No pulse
– No respirations over 1 minute
– No response to pain
 Neutropenic Sepsis
• Neutropenic Sepsis vs Febrile Neutropenia
– Look for other signs of sepsis:
• Hypotension, Tachycardia, Decreased Urine Output,
Tachypnoea

Neutropaenic Sepsis
– Common
– Recognition of those at risk:
• ON ANY CHEMOTHERAPY
– Classically days 8-15
• Fever
• Neutrophils <1
 Neutropenic Sepsis
• Why chemo patients??
– Immunosupression from
• Malignancy
• Myelosuppression
• Chemotherapy – barrier immunity e.g Mucositis
– Sources of infection
• Decreased Mobility  chest infection
• Indwelling lines

• Common organisms
– Gram Positives(60%)
• Coagulase Negative Staph e.g. Staph Epidermidis
• Strep. Viridans
– NB staph. Aureus is relatively uncommon
– Leukamias
systemic fungal infection is much more common than in solid
tumours
 Neutropenic Sepsis
• Assess Obs (BP, pulse, temp, sats, RR)
• If deranged…
– IV access
– Septic Screen
• Urinalysis
• Blood Cultures – peripheral and central
• Stool culture
– IV ABX
• Tazocin 4.5mg tds (Penecillin + Tazobactam)
• Vancomycin 1g b.d.
– Resuscitate
• IV fluids
• Oxygen if needed
– CXR
– Consider ITU referral
– Consider growth factors if haemodynamically unstable or persistent neutropenia

• Most will be haemodynamically stable so you can take a full hx including:

chemo, use of phrophylactic abx or growth factors, specific symptoms
(cough, dysuria etc.) and you can examine them for foci of infection
especially INDWELLING LINES / CATHETERS
 Spinal Cord Compression
• Most are THORACIC
• Affects 5% with cancer
• 30% of those with SCC survive 1 year
• Symptoms:
– Band-like back pain
– Worse on coughing & lying flat
– Motor loss and weakness
– Sensory changes one or two dermatomes below lesion
– Sphincter disturbance (urinary retention & O’F’ incontinence)
– Spinal Shock – reflexes won’t really be brisk and up going  it’ll be a
mess of neurological signs
• Common causes are:
– Prostate Ca
– Breast Ca
– Myeloma
– NHL
– Renal Cell
 Spinal Cord Compression
• Investigations
– MRI

• Management
– High dose steroids
• E.g dexamethasone  reduces oedema
– TED stockings + prophylactic LMWH
– If only one level involved ?surgical stabilisation
– Radiotherapy if surgery unsuitable
• Requires clinical oncologist
• 20 fractions over 5 days
 5% of paraplegic regain ability to walk
 35% of paraparetic regain ability to walk
NEED TO MAKE DIAGNOSIS EARLY
 Hypercalcaemia
• 10-20% of those with solid tumours
• Malignancy is the commonest cause in
hospital!
• Commonest causes are…
– Breast Ca
– Lung – esp Squamous Cell  PTH secretion
• Get a PTH done before Rx!
– Myeloma
– Any cancer with Bony Mets
 Hypercalcaemia
• Normal Ca is…
2.12 to 2.65
Remember to CORRECT FOR ALBUMIN
I.e. 0.02 per gram of albumin away from 40 (normal
albumin is 40)
E.g. If albumin = 20 & calcium is 2.6,
corrected calcium is (0.02*20) +2.6 = 3
Low albumin  higher calcium
High albumin  lower calcium
• Mild 2.65 – 2.9
• Moderate 3 – 3.4
• Severe >3.4
• Symptoms correlate best with rise, rather than absolute
calcium
 Mechanism of Hypercalcaemia
1. Osteolytic Lesions
2. Production of PTHrP (PTH related protein)
– Breast ca
– SCC of the lung (a type of NSCLC)
3. Production of tumour calcitriol (Vit D3)
– Usually in NHL or HD
– responds to steroids
• Common in non-metastatic ca
4. Increased bone resorption
5. Increased renal resorption and phosphate excretion
 Hypercalcaemia
Symptoms
• Moans
– Not feeling well, constipation
• Groans
– (abdo pain, GORD)
• Stones
– (kidney)
• Bones
– (bone pain)
• Psychiatric Overtones
– (lethargy, depression, memory problems)

Investigations
• PR
• Breast Examination
• Bloods: U&E, PTH CR, PSA, Myeloma Screen
• CXR, Bone Scan
 Treatment of hypercalcaemia
• Get a PTH done before Rx!

• IV fluids – usually 3 litres of saline (Na and Calcium are

coexcreted)
+/- loop diuretics later on

• Bisphosphonates
– Usually iv pamidronate or zoledronic acid
– Ibandronate is the drug of choice in renal failure as the others
are reno-toxic
– NB. Aminobisphosphonates also have anticancer effect –
Zoledronic Acid in Breast Ca

• Monitor renal function and recheck calcium

 SVC Obstruction
• Symptoms of SVCO
– Swelling of face – esp. periorbital oedema
– SOB
– Cerebral Oedema with headache, worse on stooping
– Cough
– Visual changes
– Dizziness and Syncope
– Neck swelling

• Signs of SVCO
– Venous Distension
– Pulseless raised JVP
– Suffused injected conjunctivae
– Cyanosis
– Rapid breathing
– Non-pulsatile distension of neck veins
 SVO Obstruction
• Pathophysiology
– Pressure from tumour esp. apical lung
– Direct Spread
– Intraluminal thrombus

• Causes
– Carcinoma of the bronchus 65-80%
– Lymphoma 2-10%
 SVCO – What to do? AHHHH
• Don’t ahhhh!
• A, B, C
• If stridor get help – consider intubation, urgent stent
• Hx looking for risk factors
• Past Hx of Malignancy?
• Examine the patient
• Steroids 8mg of dexamethasome b.d.
• Dyspnoea
– Oxygen
– V. bad  oromorph (small doses)
• Investigations
– Bloods including clotting, CXR / CT, Sputum and pleural
cytology
– FNAC of palpable LN
– Doppler/ Venogram of SVC
 Treatment of SVCO
• Chemo (if chemo sensitive)
• Radiotherapy
• Stenting
– Increasingly used 1st line
 Imaging in Oncology
• Diagnosis
• Staging
• Assessing Response to Treatment
• Diagnosis of Relapse

• Evaluating the Complications

– Primary disease
– Treatment regimes
 Plain Films
• Can’t stage the disease but can make certain
diagnoses
– E.g. Osteosarcoma, Canon Ball Mets (e.g. from renal
tumour), Large Bowel Obstruction, Vertebral Body
Metastases

• Two views (PA & lateral)

 Assess location of lesion

• Remember: cavitating lesions on CXR are not

tumours!
 Plain Films with Contrast
IVU (Intravenous Urogram)
– Give iodinated contrast media
– Excreted by tubules and filtered via glomeruli
– Demonstrates the renal cortex, collecting system, ureters and
urinary bladder
– Diagnosis of Renal Tumours and urothelial lesions

Barium Studies
– Young or Old  Endoscopy instead to get biopsy
– To diagnose tumours of the GI tract
• Barium Enemas
• Barium Swallow
• Barium Meal
– Barium (inert material) Coats Mucosa
– Distension with air or gas
• Calcium Carbonate + Lemon Juice is used to inflate the stomach
– Unable to stage dx
 Staging Tumours
• Cross Sectional Imaging

– Ultrasound
– CT
– MRI
– Positron Emission Tomography (PET)
 Ultrasound
• Versatile and portable
• Safe  paeds
• Relatively non-invasive
• Real Time Examination
– Blood flow / muscular function
• Disadvantages
– Operator Dependent
– Cannot image through bone or gas
• Skull - USS the brain in neonates due to fontanelles
• Gas within the stomach  obscures view of pancreas
– Difficult in fat patients as USS beam attenuated
– Clinicians find hard copy images difficult to interpret

• Screen for malignancy

– High risk patients
• Screening for Ovarian Ca in patients with family history
• Screening for Hepatocellular Carcinoma in patients with Cirrhosis
• Screening for Renal Ca in patient with VHL
 Ultrasound
• Screen for malignancy
– High risk patients
• Screening for Ovarian Ca in patients with family history
• Screening for Hepatocellular Carcinoma in patients with Cirrhosis
• Screening for Renal Ca in patient with VHL

• Assess abdominal viscera

• Evaluating Focal Liver Lesions
– Solid vs cystic

• Localising Fluid
– Pleural
– Ascites

• US guidance
– FNA
– Biopsy
– Drainage
 Ultrasound
• Wide Variety of Probes:
– Curved and linear probes
• Routine examinations
– Intra operative
• Look at liver for mets
– Echo-endoscope
• To view… Pancreas, Oesophagus, Rectum
– Endocavity probes
• Trans rectal  prostate
• Trans anal
• Trans vaginal  uterus and ovaries
 Doppler to assess blood flow
• Vessel Patency
– Deep Vein Thrombosis
– SVC
– IVC – liver lesions involving the IVC are non-
resectable

• Abnormal Vasculature
– Ovarian Ca
– Breast Ca
 Computed Tomography
• Advantages
– Greater sensitivity than US
– Can image through gas and bone
– Rapid scan times
– Reproducible images – can compare temporally
– Clinicians understand the images

• Disadvantages
– CT scanners more expensive than ultrasound
– High dose of ionising radiation
• 1CT = 450 x-rays
– Problems in paeds e.g. Wilms images
 Adults with skin tumours and lymphomas
– Iodinated contrast media
• 1:400 urticaria
• 1:4000 bronchospasm  steroids and nebs
• 1:500000 anaphylaxis
 CT
• Diagnosis of ca
• Assessing operability
• Local staging
– Local invasion
• Nodal Staging
• Distant spread
– Mets to lung, bone, liver, brain, peritoneum
• Evaluating complications of disease
 Pre-operative Imaging
• Where is the tumour?
• Is it resectable surgically?
• Are there mets anywhere else that would
preclude surgery?
• Is pre-operative down-staging of disease
required?
 MRI
• Current scanners 1.5-2T magnets
• Advantages
– No ionising radiation
– Good soft tissue contrast
– Sensitive
– Multiplanar imaging
• Can do coronal & oblique as well as axial
– Volume imaging
• Disadvantages
– Expensive
– Slower than CT
• Long scan times
• Need to lie still
• Repeated breath holds
– Noise
– Claustrophobia
• ~5% patients
 MRI
• Safety Issues
– Intraorbital metallic foreign bodies
– Pacemakers
– Clips, stents, prostheses
• Can heat up  thermal burns if left person in there
– Pregnancy (not in 1st or 2ndtrimester)

• However, it is the imaging modality of choice in…

– Brain and spinal cord
– Bone inc. spine
– Pelvis
• Prostate Ca
• Rectal Ca
• Ovarian, Cervical and endometrial cancer
– Head and Neck
• Floor of the mouth / nasopharynx
 MRI
• T1 weighted
– Anatomy
– T1-weighting causes white matter to appear
white, and gray matter to appear gray,
while cerebrospinal fluid (CSF) appears…
dark

• T2 weighted
– Pathology
– Water structures are easy to see in t2
• cerebrospinal fluid is white
– White matter is grey and grey matter is white
 Nuclear Imaging
• Functional imaging
• Radionucleotide isotopes which emit
gamma rays
– Technicium 99 (NB half life = 8 hours)
– Iodine 125
– mIBG
– Octreotide (somatostatin analogue secretion)
• Imaging taken with a gamma camera
 PET scanning
• Uses radionucleoides that emit positrons
• Any metabolically active cells show up
– Can’t do any activity before a PET scan or muscle lights up
– Fusion of CT and PET scans enable us to see if a specific lesion is
benign or malignant
• Images acquired with
– A double headed gamma camera
– A dedicated PET scanner
– PET / CT scanner
• 18F – fluorodeoxyglucose (FDG) is used for 98%
(glucose analogue  krebs cycle)
– Lymphoma
– NSCLC
– Oesophageal Ca
– Colorectal Ca Mets
• 11C-Choline
– LN involvement and one metastases in prostate cancer
 Histopathology
• Specimens take different amounts of time to process and
in theory can be processed in…
– Cytology (few minutes)
– Frozen Sections (Quick – as little as ten mins as sections are cut
in the cryostat)
– Biopsy (few hours)
– Surgical Specimens (few days)

• Classification of human tumours is based on

“HISTOGENESIS”
– Refers to the presumed cell of origin
• NB: ANAPLASTIC = v. poorly differentiated tissue that does not
resemble any normal tissue
 Technique
• Fixation
• Kill cells quickly (Biopsy – formulin, Cytology – Air Drying)
• Gross Description and Sampling
• Size & weight of specimen
• Description of lesion (colour, size, distance to resection
margin, necrosis, depth of infiltration e.g. whether colonic
tumour has breached serosis)
• Processing
– Dehydration (overnight c formulin, alcohol or xylene)
Embedding in Parafin Wax  Cutting into 2um
sections  staining  Mounting  Examining
• Reporting
 Supplementary Techniques
• Special Stains
– Collagen, elastic fibres, iron, amyloid, microorganisms
• Immunohistochemistry
– Detecting specific proteins in cells or tissues
• Molecular Pathology
– Gene mutation analysis; FISH; detections of specific
translocations
– Diagnosis: Specific Translocations in Sarcomas (Myxoid
Liposarcoma, Synovial Sarcoma, Ewing’s Tumour)
– Predict response to drugs:
• KIT in GIST
• EGFR2 in breast adenocarcinoma
• RAS in colorectal adenocarcinoma
 Carcinomas Vs Sarcoma
CARCINOMA SARCOMA
Derived from aEpithelium bConnective Tissue
) )
Benign / Malignant c)
Always Malignant dAlways Malignant
)
More common? eCommon f)Rare
)
Spread via gLymphatics hBlood
) )
Pre-malignant i Yes j)No
)
phase?
Age onset k)
Older patients l)Younger Patients
 Grading
• Most commonly used is based on the degree of resemblance to the original tissue:
– Well differentiated
– Moderately differentiated
– Poorly differentiated
– Anaplastic

• Some tumours have a special grading system

• Name the grading system for the …
– Prostate
 Gleason Grading
– Breast
 Bloom & Richardson
– Kidney
 Fuhrmann Nuclear Grading

Dysplasia – Pre-malignant change of epithelium that does not revert back to normal if
stressor taken away. It is clinically significant and is associated with
Increased cell number
Nuclear Abnormalities (e.g. hyperchromasia & pleomorphism)
Abnormalities of cellular differentiation
Metaplasia – Pre-malignant change of epithelium that does revert back to normal if
stressor taken away
 Staging
All TNM staging is recorded in guides published by UICC

T
• Size /depth of tumour
• T to T3 or 4
Colorectal Adenocarcinoma
• pT Primary Tumour
• pTX Primary tumour cannot be
assessed
• pT0 No evidence of primary
tumour
• pT1 Invades submucosa
• pT2 Invades muscularis
propria
• pT3 Invades subserosa
• pT4 Invades other organs /
peritoneum
Gastric Adenocarcinoma
• TX Primary tumour cannot be
assessed
• T0 No evidence of primary
tumour
• Tis In Situ (intraepithelial)
• T1 Invades submucosa
• T2 Invades muscularis
propria
• T2b Invades subserosa
• T3 Invades serosa (visceral
peritoneum)
• T4 Invades adjacent
structures – colon, spleen, liver
 Staging
N
• For regional lymph nodes found in the resection
specimen
• Stage varies depending on site / number of positive LNs

Colorectal Adenocarcinoma Gastric Adenocarcinoma

• pN Regional LNs
• pNx Regional LNs cannot be
assessed
• pN0 No regional LN mets
• pN1 Mets in 1 to 3 regional LNs
• pN2 Mets in 4 or moreregional
Lns
• pN0 No regional LN mets
• pN1 Mets in 1 to 6 regionalLNs
• pN2 Mets in 7-15 regionalLNs
• pN3 Mets in 16 or
more regional LNs
*Ideally at least 15 nodes should be
recovered from a gastric ca resection
 Staging
M
• For distal deposits, usually not present in the main
resection specimen but eventually biopsied at time of
surgery
• pMX Distant Mets cannot be assessed
• pM0 Not distant mets
• pM1 Distant Mets

Remember Not all tumours are graded purely with TNM

- Colorectal  Dukes Staging (A, B or C)
 Six Steps to Cancer
1. Self-sufficiency in growth stimuli
2. Insensitivity to inhibitory stimuli
3. Evasion of apoptosis
4. Immortalisation (do not age)
5. Neoangiogenesis
6. Invasion and metastasis
 1. Self-sufficiency in growth stimuli
• Normally cells need extracellular growth factor ligands to bind cell
surface receptors to cause growth. These ligands cause reversible
phosphorylation of tyrosine, threonine or serine residues on the
receptor. This causes downstream signalling in enzyme effectors
(intracellular transducers), then to non-enymatic second
messengers (phosphorylated proteins cascade) in the cytoplasm
and finally to nuclear transcription activators. This cascade causes
amplification

• Cancers can achieve self sufficiency by

– Over producing growth factors
• E.g Glioblastomas produce platelet derived growth factors
– Over producing growth-factor receptors
• E.g Epidermal Growth Factor Receptor (EGFR/erbB) in Breast
Cancer
– Mutations of the receptor or components of the signalling
cascade that are constitutively active
• E.g. Mutations of Ras in lung and colonic cancers
Malignant cell growth is associated
with loss of…
1. Density dependent cell growth
• Once normal cells reach a finite density they stop
growing. Cancer does not  necrotic centre
• A tumour that exhibits density dependent
inhibition is benign
2. Contact inhibition of movement
• Normal cells will move away from each other
when they make contact
3. Anchorage dependence
• Normal cells need contact with a substratum for
growth, malignant cells may not
4. Adhesion
 Metastasis
• Multifactorial process
– Invade beyond normal tissue boundaries
• Down regulation of E-cadherins
– Detach from primary tumour
– Enter vascular or lymphatic vessels
– Adhere to endothelium and exit from the circulation
– Local tissue invasion and induction of angiogenesis -
“the angiogenic switch” allow tumours to grow >1mm
– “The glyclytic swtich”
 Invade beyond normal tissue boundaries
Down regulation of E-cadherins
• Downregulation of E-cadherins is common in malignancy
indicating loss of cell attachment is important for invasion
• Loss of adhesion is not just interaction of the cells; there
are knock-on effects:
– Epithelial cells are held together by junctional complexes;
adherens-type junctions –interactions between E-cadherin
molecules that span the plasma membranes of adjacent cells. E-
cadherin molecules link to actin cytoskleton through E-cadherin
associated proteins called “β-catenin”.
– If Cadherin is lost free β-catenin is lost in the cytoplasm. This is
dangerous!
a complex involving a APC protein normally binds the free β-
catenin
When the APC gene is mutated (e.g. colorectal ca) β-catenin
accumulates and binds to transcription factors and switches on
c-myc (mutated in Burkitt’s lymphoma)
 Tumour Invasion
• Requires degrading enzymes called …
“matrix metalloproteinases”
– Normal enzymes involved in tissue
remodelling
– May also be secreted by tumour cells, but
also by stroma (e.g. fibroblasts), therefore
non-malignant cells are actually critical in the
development of many cancers.
 Adhesion to endothelium
• As tumour cells enter small capillaries they
slow by size restriction
• Endothelia have adhesion molecules
known as “Selectins” (e.g. P,L,E) which
can bind tumour cells. Selectins on
epithelial cells interact with Integrins on
tumours cells.
Colonisation and survival at distant
site
• Growth factors differ at different sites of the body
 “soil and seed” hypothesis

• Breast cancer cells expressing CXCR4 find

match in lung due to expression of CXCL12
• Melanoma cells express CCR10 and find match
in skin because of expression of CCL27
 The Glycolytic Switch
• Many cancer display upregulation of glycolysis – “the
glycolytic switch”
• The glycolytic switch occurs as the tumours are
operating under anaerobic conditions.
• They do glycolysis very efficiently by up-regulating
glucose receptors
 less glucose becomes available for normal cells which die
 invasion and growth
• Glycolysis produces lactic acid so the tumour becomes
acidic
 Other cells are pH sensitive and die  invasion and growth

PET scanners use a glucose analogue FDG to show where

glucose is being taken up the most and therefore the site
of any cancer >0.8cm3.
 The Angiogenic Switch
• Avascular tumours cannot growth beyond 2-3mm without
angiogenesis – failure of tumour cells to stimulate angiogenesis is
responsible for long-term dormancy
• Angiogenesis depends on the balance of pro- (e.g. VEGF, FGF) and
anti- (e.g. Thrombospondin1) angiogenic factors
• Unlike normal vasculature, tumour vasculature
– Does not under go quiescence
– Is chaotic and leaky

• Angiogenesis inhibitors:
– COX2 inhibitors down regulate VEGF and FGF
– Avastin (bevacizumab) approved for treatment of colorectal cancer (anti-
VEGF)

• Vascular Disrupting Agents

– 2 groups:
• Combrestatins  targets B-tubulin
• DMXAAs
– Both disrupt the actin cytoskeleton of endothelial cells
 Breast Cancer
• Incidence
• Risk Factors
• Screening
• Diagnosis
• Staging
• Grading
• Management
 Epidemiology
• Commonest female cancer in europe
– Lifetime risk in females 1 in 9
• 20% of all malignancies
• Incidence is increasing by 1% each year
– More so in low-risk populations
• Risk correlated risk income per capita
– Much higher rates in western than eastern
cultures
• Male breast ca is rare – 300 cases per yr
• Age
Aetiology
– V. Rare <20, Rare <30
Male breast cancer may be associated with Kleinfelters Syndrome
(47– XXY)
Incidence doubles every ten years until th menopause
– After 50 the rate slows and in some countries plataues
Peak incidence is ten years later than in women
• Oestrogen
– Early menarche & late menopause
– The OCP
– HRT
– Nulliparity or late pregnancy
• Genetics
– Accounts for 10% of breast ca & 20% male breast ca
• Radiation
• Atypical Epithelial Hyperplasia (Benign Breast Disease)
– 4x increase in risk
• Diet
– High dietary fat & obesity
– Alcohol
Smoking is NOT a risk factor
 Genetics of Breast Ca
• Women who inherit a mutated copy of BRCA1 or BRCA2
have an elevate lifetime risk – 87% by age 80!
– Particular risk of premenopausal breast ca (esp. before age 40)
– Also at increases risk of ovarian cancer (especially BRCA1)
– Male carriers are at risk of prostate ca and for BRCA2 breast ca.
– Common in Ashkenazi Jews
• Also associated with mutations in PTEN (Cowden
disease) & MSH1 or MSH2 (HNPCC – Hereditary No-
polyposis Colorectal Cancer) & p53 (LiFraumeni-
Syndrome)
• Currently the following options are avaliable to women at
moderate or high risk (risk determined by breast and ovarian cancer in relatives)
– Prophylactic Bilateral Subcutaneous Mastectomy
– Screening
 Pathology
• Breast cancer is more common In the left breast
• Around 50% arise in the upper outer quadrant
• Commonest pathology is ductal carcinoma

Ductal carcinoma In Situ

• Remains in the confines of the ductal basement membrane
• 90% carcinomas arises in the ducts
• Begin as atypical proliferation of ductal epithelium that eventually fills and
plugs the ducts with neoplastic cells
• Localized DCIS is impalpable but often visible on mammography as an area
of microcalcification.
• Invasive progression in ~30-50%

Lobular carcinoma In Situ

• These pre-invasive lesions carry a risk not only of ipselateral invasive
lobular carcinoma but also contralateral breast ca!
• Typically are neither palpable or contain microcalcification
 Pathology
Invasive Ductal Carcinoma
• Accounts for 75% of breast ca
• The malignant cells are associated with a stroma that
can be dense (scirrhous carcinoma)
• Tumour invades through breast tissue into the
lymphatics and vascular spaces, to gain access to the
regional lymph nodes (Axillary & Internal Mammary)
and the systemic circulation.
• Systemic spread most commonly involves bone, lung or
pleura, liver, skin or CNS.
• Histological grade is assessed from three features and
predicts tumour behaviour:
1. Tubule Formation
2. Nuclear Pleomorphism
3. Mitotic Frequency
• Biological markers (eg. HER2) are useful as a
prognostic indicator and a guide to therapy
• Oestrogen and Progesterone status is assessed by
immunocytochemistry
 Pathology
Ductal Carcinoma of Special Type
• Pathological Variant all have relatively good prognosis
– Medullary Carcinoma
– Tubular Carcinoma
– Mucinious Carcinoma
• Paget’s disease of the breast is ductal carcinoma with
involvement of the skin of the nipple and areola

Invasive Lobular Carcinoma

• Account for 5-10% of breast ca.
• ~20% develop contralateral breast ca
• Unusual patterns of spread
– Propensity for PERITONEUM, MENINGES, OVARIES &
UTERUS

NB: You can get mixed lobular and ductal carcinoma

 Prognostic Factors
• Size
• Grade
• LN status!
• Presence of vascular invasion
• HER 2 +ive  worse prognosis
 Prognostic Indicators
• Nottingham Prognostic Indicator
– 0.2 x tumour size (cm) + grade (1-3) + axillary node
score (1-3)

– Axillary Node Status

• No nodes =1
• 1-3 Nodes =2
• >3 Nodes =3
– NPI
• <3.41 Good prognosis
• 3.41 – 5.4 Intermediate prognosis
• >5.4 Poor prognosis
 Presentation
• Abnormal screening mammogram
• Breast lump or thickening
• Axillary tumour
• Breast skin changes:
– dimpling, puckering, erythema
• Nipple changes:
– inversion, discharge, rash (Pagets disease)
• Persistent breast tenderness or pain
• In frequently symptoms from metastatic dx –
back pain
 Management of Non-invasive
Breast Cancer
Options
– Simple Mastectomy
• Stnd rx for large or multifocal non-invasive ca
– Wide excision alone
• Much worse reoccurrence (20-30% in 5 yrs- ½ of which are
invasive)
– Wide Excision and post op radiotherapy
• Whole breast is irradiated
• Re-occurrence rate <10% in 5yrs)
– Adjuvant hormone therapy
• Controversial – two large trial contradict each other
 Surgical Management
• Mastectomy
– Large tumour (>4 cm)
– Small breast
– Tumour involving the nipple
– Patient choice
– Absolute indication: Multifocal Tumour

– Risk reducing mastectomy in high risk pt

• BRCA1 & BRCA2  80% life time risk
• Mastectomy reduces risk by 90% cf. Tamoxifen
60% (but tamoxifen has lots of SEs!)
• Strong family Hx
• Extensive pre-cancerous disease (DCIS >5cm)
 Surgical Management
• Wide Local Excision
– Small tumours <4cm
– Margins should be clear
• 5mm in invasive carcinoma
• 1cm in DCIS
– DCIS needs wider margins as it is difficult, even with
histological techniques, to accurately assess the margin
of the tumour
• Some studies are showing that everything only
need 2mm margins now
Reconstruction
• According to NICE ALL patients with mastectomy
should be offered reconstruction
– Immediate – DCIS
– Delayed of possibility of reoccurance
• In wide local excision, those with small breasts and
central tumours should be offered reconstruction
• Techniques
– Tissue Expander (poor cosmetic results)
» Don’t know the life of implants
» Cause scarring  can contract and become painful
– Lat dorsi flap – good (most common)
– TRAM / Dieppe flap (from tummy) = “tummy tuck”
(TRAM = Transversus Abdominus Rectus Muscle)
 Axilla
Axillary Staging
– The most important prognostic factor is LN
involvement
– Options:
• Sentinel Node Biopsy
– Inject blue dye and radionucleotide dye into upperouter
quadrant – look (blue and gamma camera) during the op
– Sentinal Node removal  lower risk of lymphoedemaand lower
risk of shoulder stiffness
• Axillary Node Sampling (any 4 nodes)
• Axillary Node Clearance (15% get lymphoedema)
– Most just remove Level 2 LNs (Posterior to Pec Minor),
sometimes also remove Level 1 (Lateral to pec minor) and
Level 3 (medial to pec minor)
Management of Early Breast Ca
• Neoadjuvant Chemo or Hormone Therapy
– Allows assessment of response to rx –
impossible with adjuvant chemo.
– Can downstage tumour which might allow
breast conserving surgery
– But… delays local surgery

– No difference in survival pre / post op chemo

Management of early Breast ca
• Adjuvant Chemo
– Gold Standard Treatment is E-CMF
= Epirubicin + Cyclophosphamide + 5-Fluorouracil
– In HER-2 positive patients you can use Trastuzimab (Herceptin) –
Monclonal Antibody that blocks the HER-2 receptor  +6-
9months
• Adjuvant Hormone (Endocrine) Therapy
– Only used in ER+ive tumours where oestrogen will drive the
growth of the tumours
– Premenopausal Tamoxifen - block the oestrogen receptor on
cancer cells.
Increases incidence of endometrial cancer (x2) & thrombogenic
Interestingly reduces incidence of second primary breast tumour
and maintains bone mineral density in postmenopausal women
– Postmenopausal  Aromatase Inhibitors (e.g. anastrazole,
eximestane)
– Block peripheral Oestrogen production (Aromatase converts
Androgens into Oestrogen). This won’t work if the ovaries are still
 Adjuvant Radiotherapy
• Reduces risk of reoccurance after conservative surgery (wide local
excision) from 30% to <10% in 10 yrs
• Can be used as palliation in bone and brain secondaries

Late Hazards Early Hazards

•Breast changes (telangiectasia, •Inconvenience
fibrosis, slow shinkage for 3-4 years) •Tiredness
•Radiation Pneumonitis (responds •Breast swelling
well to steroids) •Breast pain
•Osteoporosis / rib fracture •Inframammary fold burn
•Second cancers (sarcoma)
Current Research
If irradiate the axilla:
•Lymphoedema Fractionation
•Restricted Shoulder Movement
•Brachial Plexopathy Intraoperative Radiotherapy
- Numbness, pain,
weakness
 A note on anthracyclins
• Anthracyclins (e.g. Epirubicin) are the most
effective treatment in breast cancer
• They direct their effects at activating Protein
Kinase C-mediated cell signallng pathways
• Cardiotoxicity
– Cumulative cardiotoxicity is specific to anthracyclins
and is caused by free radicals in the heart
– Dose related risk of HEART FAILURE
• Anthracyclin use
– Doxorubicin and Epirubicin are used in treatment of
Breast Ca, sarcoma and haematological malignancies
– Daunorubicin and idarubicin (oral) are used to treat
acute leukamias
 Breast Cancer Prevention
• There is a 50% reduction in breast cancer with
Tamoxifen but due to the thrombogenicity and
the increased risk of endometrial cancer
Tamoxifen is not viable prophylaxis
• Raloxifene (a SERM “selective oestrogen
receptor modulator, used in osteoporosis)
reduces breast cancer risk
• Aromatase Inhibitors are in a trial as breast
cancer prevention
 Management of Locally Advanced
- Primary Systemic Treatment +
radiotherapy

– Aromatase Inhibitors if ER-positive

(Anastrazole, letrazole or exemestane)
Better than Tamoxifen in advanced dx

– Maximal response radical radiotherapy

(Directed at the breast, axilla and supraclavicular fossa)
 Management of Metastatic
Breast Cancer
• All palliative
• ER positive bone dx  better prognosis
• ER negative visceral dx  worse prognosis

• Endocrine Therapy
– Premenopausal  LHH agonist + tamoxifen
– Postmenopausal  aromatase inhibitor
• Chemotherapy
– For visceral dx and ER negative tumours
• Immunotherapy
– HER-2 (a growth factor receptor) + ive  poor prognosis
– Give trastuzumab

• Bone M et s  Palliative radiotherapy + Bisphosphonates

 Childhood Cancers
• Childhood ca incidence is stable at ~160/yr
– 1/3rd leukaemias - ALL accounts for 24% under 15
– 1/5th CNS
– 7% Neuroblastomas
– 4% Wilm’s Tumour
– 2% Bone Tumour – osteosarcoma & Ewing’s

• Teratogenicity
– Many treatments are teratogenic.
– Most BP treatment is except Labetolol and
– Oestrogen exposure in early pregnancy causes girls
to develop adenocarcinoma of the genetal tract
 Colorectal Cancer
• Fourth commonest cancer worldwide
• Affects men and women almost equally
• Environmental factors (diet) play a major role in the
aetiology
• A minority (8%) of cases are associated with genetic
predisposition syndromes
– FAP
– HNPCC
• Almost always adenocarcinoma
• Loco-regional LNs tend to be involved before the
development of disseminated disease.
• In rectal cancer there is also a propensity for the tumour
to infiltrate laterally into the peri-rectal fat and LNs.
 Aetiology
• Environmental
– Diets high in animal fat and red meat
– ?influence of processing, type and cooking of meat
• Genetic
– Mutated K ras
– Dominant inherited disorders (15%)
• Familial Adenomatous Polyposis (FAP)
 APC gene. Desmoid Tumours
• Hereditory Non-polyposis Colorectal Cancer (HNPCC)
 Mismatch Repair genes (MSH2 & 6, MLH1, PMS1 & 2)
– Autosomal Recessive
• MYH Polyposis
• Dysplasia is common in Ulcerative Colitis
• It is widely believed that adenomatous polyps are the
precursors to the majority of colorectal cancers
– Tubular, Villous or Tubulovillous.
– Villous  bigger & more prone to develop into ca
 Familial Adenomatous
Polyposis FAP
• <1% of CRC
• Inherited mutation of APC gene (tumour
suppressor gene on chr 5)
– 30% new mutations
– Truncated APC gene product – loss of gene function
• >100 adenomatous polyps in colon and rectum
on colonscopy
• Cancer develops ~39years and it ALWAYS
occurs (inevitable) unless treated
– Can do prophylactic colectomy at the age 14-16 when
APC mutation is found / multiple polys are present
 Familial Adenomatous
Polyposis FAP
• Management
– DNA testing
• Those at 50% risk and family mutation known, offer mutation testing at age
10-12 years
– Low Risk  reassurance, stop screening
– High Risk  Lifelong surveillance, chemoprophylaxis (CAPP1)
• Gene carriers or those at 50% risk where family mutation unknown
– Start annual colonoscopy from 10-12 years
• When mutation present / polyps found
– Elective colectomy
Remember if the APC gene is not mutated they still have a risk of cancer (just the normal
population risk!)
• Extra-colonic manifestations
– Desmoid Tumours (locally invasive; usually abdominal)
– CHRPE (Congential Hypertrophy of Retinal Pigment Epithelium)
 “bear track” at the back of the eye
– Sebaceous Cysts
– Jaw Cyst (osteomas)
– Upper GI (duodenal polyps and cancers)
 Familial Adenomatous
Polyposis FAP
Knudson Two-Hit Model
• Those with “inherited cancer” affecting
tumour suppressor genes already have
one mutation at birth. Therefore if it takes
20 years for another mutation to occur
then they are predisposed to cancer at a
young age
• Those with sporadic cancer will take twice
as long to develop cancer as they need
two mutations to occur.
 Familial Adenomatous
Polyposis FAP
• Key Points
– CRC risk is 100% in untreated FAP patients
– Genetic testing identifies most APC mutation
carriers
– Endoscopic surveillance and prophylactic
colectomy can improve survival in at-risk
patients
– Non-carriers can be spared anxiety and the
need for increased surveillance
 Hereditary Non-Polyposis
Colorectal Cancer
• (HNPCC)
HNPCC = Lynch II Syndrome
• 3% of all CRC (more common than FAP)
• Dominant Inheritance
• Diagnosis from family hx (not in individual with CRC)
• Penetrance ~80%
• Germline mutations in genes encoding proteins of DNA
mismatch repair system (MMR)
– MMR failure leads to Microsatallite Instability
– MLH1, MSH2, MSH6, PMS1, PMS2
• Early but variable age of diagnosis (~45yrs)
• Polyps: adenoma carcinoma sequence
• At risk for other types of cancers
– endometrium, ovary, stomach, urinary tract, small bowel, bile
ducts, sebaceous cyst tumour
 Hereditary Non-Polyposis
Colorectal Cancer
(HNPCC)
Amsterdam Criteria for Diagnosis HNPCC
• 3 or more relatives with CRC
• Two or more generations
• One CRC by age 50
• One case a primary degree relative of the others
• FAP excluded

NB: Modified Amsterdam Criteria: substitute endometrial

cancer for CRC
 Hereditary Non-Polyposis
Colorectal Cancer
(HNPCC)
Surveillance
• In known gene carriers and those at 50%
risk
– Annual Colonoscopy from age 25
– Annual gynae surveillance in women from age
30
– (Endoscopy if FHx of stomach cancer; renal
screening if FHx of renal cancer)
 Hereditary Non-Polyposis
Colorectal Cancer
(HNPCC)
Key Points
• Tissue based testing (IH & Microsatellite
Instability studies) provides clues as to whether
the mutation is present
HNPCC is the only familial ca where tissue based
testing is currently available
• Genetic testing can identify mutation carriers:
– At risk individuals  colonoscopy surveillance 
improves survival
– Non carriers  spared anxiety
 MYH
Familial Polyposis Syndrome
• Autosomal Recessive Inheritance
• 10- 100s polyps (<1000)
• Mean age at cancer diagnosis 49 years
• Unlike FAP there is no other cancers
associated
 Colorectal Cancer Symptoms
• Left Colon • Right Colon
– Altered bowel habit – Anaemia
– Blood and mucus per – Mild diarrhoea
rectum – Abdominal pain
– Abdominal pain – Palpable mass

• Rectum
– Fresh bleeding
– Mucus
– Tenesmus
– Pencil thin stools
DOH referral guidelines. Refer If…
• At any age…
– Rectal bleeding with a change in bowel habit to looser
stool &/or increased frequency of defecation (>6/52)
– Definite palpable right sided abdominal mass
– Definite palpable rectal (not pelvic) mass
– Iron-deficiency WITHOUT obvious cause
– Abdo pain with no evidence of obstruction
• Over sixty…
– Rectal bleeding alone
– Change of bowel habit to looser stools &/or increased
frequency of defecation >6/52
 Investigations

• Over 70% occur within reach of a sigmoidoscope

(rectum and left colon)
– See Villous adenomatous polps 
• Rigid sigmoidiscope +/- biopsy
• Flexible sigmoidoscope
• Colonoscopy
• Barium Enema
• CT scan (GI protocol)
• CT colonography
– Helical CT scan with bowel empty and distended with air
 Dukes Staging
• A = tumour limited to the wall
• B = tumour extending into the wall
• C1 = Perirectal / colonic LN mets
• C2 = Apical LN mets
• D = Tumour beyond the limits of surgical resection.

• Duke staging is comparible to TNM staging (A = I, B = II,

C= III, D = IV)

• Bowel metastases have a predilection for the LIVER due

to the PORTAL CIRCULATION.
 TNM staging
• T1- in submucosa and lamina propria
 Surgery only
• T2 - into muscularis propria
 Radiotherapy pre or post op
• T3 - invasion through the muscularis propria OR
to adjacent mucosa
 Radiotherapy pre or post op or chemoradiotherapy pre-op
• T4 – invasion completely through the wall of the
colon or fixed in rectal tumours
 Chemoradiotherapy Pre-op
 Pattern of Spread
• Local
• Lymphatic
• Vascular
• Trancoelemic (rare)
– Sister Mary Joseph Carcinoma
– Ovarian transcoelemic spread often causes Krukenberg Tumours.
 Surgery
• Pre-OP
– Bowel prep is controversial
– Pre/pro biotics
– Pre-op carbohydrate loading
– Stoma care
– In rectal cancer where resection margin is likely to be positive,
give Long course chemo-radiotherapy (LCCRT) to shrink the
tumour before removal
• Aim: remove tumour with draining lymphatic supply
• Total Mesorectal Excision (TME)
– resection of tumour within intact mesorectal envelope (soft
tissue)  reduced risk of local reoccurrence
– Get pathologist to check top, bottom and lateral margins
– Previously, depending on the part of the rectum involved, would
excise the tumour and pathologist would check top and bottom
margins.  30% risk of reoccurrence
 Surgery Types
• Right Hemicolectomy
• Left Hemicolectomy
• Anterior Resection
– Upper rectum resected and anastamosis made
• Abdomino-peritoneal excision of rectum
 Barbie bum

Key Issues
- Anastomotic Leak rates (<8%)
- Local reoccurrence rates (<10%)

Rapid mobilisation and feeding following operation

- use little opiate
 Chemotherapy in Colorectal Cancer
• Fluouropyrimidines
– 5-fluourouracil is the backbone of rx
– Capecitabine
• DNA damaging agents
– Irinotecan
– Oxaliplatin
– Mitomycin C
• Agents targeting signalling pathways
– Cetuximab
• Target is Epidermal Growth Factor Receptor (EGFR)
• Agents targeting normal cells contributing to malignancy
– Bevacizumab (Anti-VEGF)
– Too expensive so experimental
 5- Flourouracil
• Remains the backbone drug for treatment of
CRC
• Inhibits Thymidine Synthetase (TS) as main
mechanism of action
• Potentiated by Folinic Acid
• Better tolerated as infusion than a bolus
• Improved survival by 3-6months
• Similar efficacy seen with oral Capecitabine
 Irinotecan
• A topoisomerase inhibitor
• Irinotecan Toxicity
– Severe late onset diarrhoea
– Neutropenia
– Mucositis

– Toxicity less used at lower dose in combination regimes

Oxaliplatin
• Causes intrastrand and interstrand crosslinks in DNA
• Inhibits DNA synthesis and transcription
 Radiotherapy
• Radiotherapy is limited mainly to rectal cancer
– Short course pre-op
– Long course pre- /post-op
– Chemoradiotherapy (long course combined with infusions of fluorouracil)
• Main indications
– Downsize inoperable tumours to render operable
– Reduce local reoccurrence rates of operable tumours (pre-op)
– After resection if tumour margins found to be involved (post-op)
• Palliation of locally advanced disease and secondaries in bone and
brain
• SEs / Complications
– Early
• Tiredness
• Skin soreness
• Diarrhoea
• Radiation Cystititis
– Long-term
• Radiation Proctitis
– Loose stools, diarrhoea, bleeding, incontinence, pain
• Infertility (f>m)
• Pelvic Pain
 Emergency Presentation
• Obstruction
– 16% of cases present with obstruction
• Perforation (less common)
• Bleeding (rarely)

• Fluid resuscitation
• Water soluble contrast enema / CT
• Day time list with experienced surgeons
• Surgical Options
– Hartmann’s Proceedure
– Resection and primary anatomosis +/- lavage
 Colorectal Liver Mets
• Disease confined to the liver in 50% of
patients dying of CRC
• Majority have multiple deposits
• Up to 25% have resectable disease
• 80% present within 2 years

• NB- resection of primary tumour confers

no survival benefit once metastasized
• CEA
– Raised  prognostically bad
– Down than up  reoccurance

• Most reoccurrences are detected by 2

years; nearly all by 5 years.
 Palliation
• Palliative resection
• Bypass
• Stent
– Usually for left sided unfit for surgery
– Can perforate
• Stoma
 Lung Cancer
• Epidemiology
– Second most common cancer in the UK (to
breast ca)
– Lung cancer is the most frequent cause of
cancer deaths in both men and women in UK
– In the UK incidence is falling due to less
people smoking
– Worldwide, incidence is increasing particularly
in developing countries as more people start
to smoke
 Lung Cancer
• Aetiology
– 80-90% of lung cancer is due to smoking
• Risk of lung cancer relates to the number of cigarettes smoked, the
number of years of smoking, early age starting to smoke and the
type of cigarette (bad = unfiltered + high-nicotine)
• Smoking in women and adolescent is increasing in the UK
– Passive smoking
– Pulmonary Fibrosis
• Diffuse
– Idiopathic e.g. Interstitial pneumonia
– Asbestos
• Previous Radiotherapy to the chest
– Rarely, inhalation of radon gas, polycyclic aromatic
hydrocarbons, nickel, chromate or inorganic arsenics
Pathology Lung Cancer
– WHO 1999 Classification
• Squamous Cell Carcinoma (30%)
– These show keratin formation and intracellular bridges (desmosomes)
• Small Cell Carcinoma (SCLC, 15-30%)
– Highly aggressive; composed of primitive neuroendocrine cells (express CD56)
– Usually spread widely at diagnosis  chemo not surgery
• Adenocarcinoma
– Often express Throid Transcription Factor in their nuclei (giving evidence for it
being a lung primary (or thyroid primary)
a. Acinar
b. Papillary
c. Bronchioalveolar
- Diffuse, grows by replacing normal epithelium
a. Mucinous
b. Mixed
• Large cell neuroendocrine carcinoma
• Mixed carcinomas
– Adenosquamous
– Mixed small cell and non-small cell
– There is evidence that lung cancers may arise from pluripotent stem cells in the
bronchial epithelium- this would explain the mixed cytology that is commonly
seen
– For purposes of management lung cancers are grouped as non-small
cell (NSCLC) or small cell (SCLC)
 Lung Cancer
• Genetics
– The majority of lung cancers have >20 genetic
alterations, acquired in a step wise fashion. These
may include:
• Oncogene Activation
– EGFR over-expression leading to stimulation of this proliferative
pathway
– Point mutation of RAS or MYC activating signal transduction
pathways
• Tumour Suppressor Gene Inactivation
– P53 (>70% SCL, 50% NSCLC)
– BCL2 – high expression in SCLC protects against apoptosis
– Genetic Predisposition
• Family Hx of lung cancer increases the risk by 2.5x even
when smoking is taken into account
• Carcinogen Metabolism
• Rarely germline mutations of Rb or p53
 Interesting Pathology in Lung Ca
• Small cell can secrete:
– ACTH  Cushings
– ADH  Retension + hyponatraemia

• SCC can secrete:

– PTH hypercalcaemia

• Paraneoplastic Effects (other ones)

– Skeletal Changes
• Finger clubbing
• Pulmonary Osteo-arthropathy
– Nervous System Changes
• Confusional state
• Cerebellar Degeneration
• Encephalolylitis
• Peripheral Neuropathy
• Myasthenia
• Myopathy
 Lung Cancer
• Diagnosis:
– A primary tumour in the lung typically forms an irregular mass on
CXR or CT. It may cavitate and so be confused for an abscess
– Due to differing treatment regimes based upon tumour type you
need cytological specimens or biopsies
• Centrals tumours are generally seen on bronchoscopy and can
generally be biopsied
• In addition specimens for cytology can be obtained by brushing the
tumour and/or washing out a bronchus with saline
• Peripheral tumours can be biopsied under CT guidance
• If there is a pleural effusion it may be possible to make the
diagnosis from malignant cells in the fluid (automatically T4)
 Lung Ca Stage
• Pathological Staging is considered to be the most accurate
• In-situ carcinomas
– Squamous carcinoma in-situ
– Atpical adenomatous hyperplasia
– Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia
• T1
– <3cm; does not involve main bronchus
• T2
– >3cm
– Main bronchus involvement but >2cm from the carina
– Extends to the visceral pleura
– Collapse or obstructive pneumonitits to the hilum of the lung but not involving the whole
lung
• T3
– Invades any of (chest wall, diaphragm, mediastinal pleura, parietal peritonium)
– Closer than 2cm to the carina but not touching
– Collapse or obstrutive pneumonitis of whole lung
• T4
– Invades any of (Mediastinum, Heart, Great vessels, trachea, oesophagus, vertebra or
carina)
– Has a malignant pleural effusion

• M1 – in the lung separate tumour nodules in a different lobe from the primary is
considered to be M1
– Common places for lung mets are…. Other sites in the lung, liver, brain, bone marrow,
adrenal gland and kidney
These TNMs are grouped into four stages I-IV with further subdivision A & B
 Mesothelioma
• Diagnosis:
– Histologically mesothelioma can show a variety of appearances.
The tumour cells can look epithelial or be spindle shaped and
resemble stromal cells (sarcomatoid)
– If epithelial they can show either solid islands of tumour cells,
form glandular structures with lumina or be papillary.
– Often they show a mixture of architechtures ch is a strong clue
to the pathologist that it is primary mesothelioma rather than
metastasid adenocarcinoma
– But always need to confirm mesothelioma by immunostaining
• The epithelial parts of a mesothelioma express the proteins
calretinin and cytokeratins 5 & 6, but are negative for the proteins
expressed on adenocarcinomas (e.g. BerEP4 antibody, E-cadherin,
carcinoembryonic antigen and for lung adenocarcinomas…TTF-1).
Mesotheliomas also often stain positive for Thrombomodulin.
 Mesothelioma

• Treatment:
– MSO-1 trial
• Showed no benefit of MVP (Mitomycin, Vinblastine, Cisplatin/
carboplatin) cf. best supportive care (ie. Palliative)
– Alimta (Pemetrexed)
• Trial compared with single agent cisplatin (criticised as
cisplatin not normal rx)
• Showed 40% response rate (v high)
NB: always give folinic acid tablets + Vit B12 injections with
Alimta
 Lung Ca Treatment
• Non-small cell lung cancer
– (SSC, Large Cell C and adenocarcinoma)
– If resectable (stage IA – IIB), lobectomy or
pneumonectomy is the treatment of choice
– Alternatively radical radiotherapy may be tried
– Chemo can be used for more advanced (IIIB-
IV) cancers but the cure rate is low.
 Lung Cancer Chemo
• Indicated for stage III & IV
• Platinum drugs + “third generation” drug
– Platinum Drugs:
• CISPLATIN
– SEs: Hair loss, GI upset, Nephrotoxic
• CARBOPLATIN
– Better SE profile generally but very myelosuppressive
– Third Generation Drug:
• Gemcytobine (Gemzar)
• Navelbine (Vinorelbine)
• Paclitaxel (Taxel)
• Taxotere (Docetaxel)

• 2ndline: (ie. After 1 course of chemo failed to induce a response)

– Taxotere (Docetaxel): Response rate ~8% or
– Erlotinib (inhibits HER-1 and αEGFR) SEs: Severe ACNE, intestinal pul
fibrosis

– Avastin (bevacizumab  inhibits VEGF) – only licensed for CRC but

may be of use in adenocarcinoma NSCLL
 Lung Ca - SCLC
Rx of Small Cell Lung Cancer
• All patients:
– Platinum based chemo 4-6 cycles if disease is responsive
– Multidrug regimes Maintenance treatment is not recommended

• Limited stage disease

– Thoracic Irradiation used concurrently with 1st or 2ndcycle of after
chemotherapy if disease is responsive

• Extensive Disease
– Thoracic irradiation may be used if there is a good response to
chemotherapy
 Von Hippel Lindau Disease
• Autosomal Dominant inheritance of a recessive
mutation - VHL gene
• The syndrome
– Tumours
• Hemangioblastomas (retina, cerebellum, spinal cord)
• Clear Cell Renal Carcinoma
• Pheochromocytoma
• Endolymphatic Sac tumour
• Pancreatic islet Cell tumour

– Further alterations
• Angiomatosis (retina and various organs)
• Cysts (kidney, pancreas)
• Polycythaemia
• Café au lait spots
 Clear cell RCC in VHL disease
• 75% of all RCC are clear cell RCC
In sporadic ccRCC 60-75% mutations in VHL
• High lifetime risk (25-45%)
• Earlier age at onset than in sporadic cases
• Frequently multicentric and bilateral RCC
• Microscopic tumours in normal parenchyma
 Treatment of VHL
• Surgery
– Non-metastatic disease: only curative rx
– Advance dx: nephrectomy + immunotherapy as palliative
procedure
• Anti-VEGF antibody: Bevacizumab
– Enhances response rate and prolongs disease control when
added to IFNα
• Multi-kinase Inhibitors: Sunitinib & Sorafenib
– Response rate 36-40%
– Prolonged time to progression and preserve quality of life
– Emerged as the predominant first-line treatment for metastatic
RCC, irrespective of risk category
 Neuroendocrine Tumours (NETs)
• Carcinoid Tumours (66%)
• Pancreatic Neuroendocrine Tumour (PETs) (33%)
– Gastrinoma (Zollinger Elison Syndrome)  diarrhoea,
malabsorption, peptic ulcer
– Insulinoma  Hypoglycaemia (autonomic and neuroglucopenic
symptoms)
– VIPoma  Watery diarrhoea and hypokalaemia
– Glucagonoma  DM, neurolytic migraory erythema
– Somatostatinoma  DM, diarrhoea
• Misc
– MEN1 and MEN2
– Neurofibromatosis type 1
– Medullary Carcinoma of the Thyroid
 Carcinoid Tumours
• Classified by embryological origin
–Foregut  bronch, thymuc, stomach, duodenum
–Midgut  Jejunum, Ileum, prox. Colon
–Hindgut  Distal colon and rectum
• Not all “functioning” ie. Producing hormone / molecules but those
that do can produce 5HT (Serotonin), ACTH, bradykinin, PGs,
histamine
• Functioning carcinoid tumours can give rise to the
carcinoid syndrome:
–Flushing and facial telangiectasia (Bradykinin)
–Diarrhoea
–Wheeze
–RVF caused by endocardial fibrosis (effect of serotonin (5HT))
• Management
– Surgical removal
– Octreotide (somatostatin analogue)
– Symptom control
 MEN-1
• Primary Hyperparathyroidism
• Pituitary Tumours
• Pancratic Neuroendocrine tumours

MEN-2a
•Pneumonic:
Primary Hyperparathyroidism
• Medullary carcinoma
Thyroid of Thyroid
(Medullary the Thyroid
Carcinoma)
• Around 30% of MCT patients have germline RET mutations (chr10)
Adrenal (Pheochromocytoma)
• Phaeochromocytoma
5
Primary Hyperparathyroidism

MEN-2b
• Like MEN 2a but without parathyroid involvement and
with mucosal neuromas (bumps on lips, tongue, cheeks
and eyelids) and marfanoid appearance
 Neurofibromatosis
• Type 1 – formerly known as Von Recklinhausens
– Multiple cutaneous fibromas
– Soft papillomas
– Café au lait spots
– Iris FIbromas
– Neuroendocrine tumours
– Much more!

• Type 2
– Not neuroendocrine tumours
– Bilateral acoustic neuromas
– Cerebral / optic nerve gliomas
– Meningiomas
– Spinal neurofibromas
 Medullary Carcinoma of the Thyroid

• Arises in parafollicular C cells (cells which

normally secrete Calcitonin)
• Tumour cells secrete: calcitonin, 5HT, ACTH,
PGs
– Hence can get Carcnoid syndrome and Cushings
• Presents in middle age usually with a firm
thyroid mass and cervical lymphadenopathy
• May occur sporadically or as part of MEN2
 Acute Leukaemia
• Epidemiology
– Peak incidence in ALL is 2-4 years
– Peak incidence in AML is >60 years
• Aetiology
– Most are of unknown cause
– Some congenital and inherited disorders confer increased risk:
• Down’s syndrome
• Fanconi syndrome (Proximal Tubular Acidosis – type2)
• Bloom’s syndrome
• Klinefelter’s syndrome (47XXY)
• Neurofibromatosis
– There is a 3-5x increased risk in identical twins
– Environmental Factors are thought to include:
• Radiation including in-utero radiation  ALL
• Benzene, inc. smoking
• Chemotherapy
• HTLV  Adult T Cell Leukaemia
 Acute Leukaemias
• Pathology
– Acute Leukaemias arise from the malignant transformation of
haemopoeitic stem cells or early stage committed progenitor
cells. The cells proliferate but fail to differentiate properly 
accumulation of blast cells in the marrow and BM failure-
pancytopaenia.
• Thrombocytopenia  bruising and bleeding
• Anaemia  lethargy
• Neutropenia  infection
– Acute Leukaemia is diagnosed when the bone marrow blast
count is >20% of nucleated cells
– Other extramedullary features can occur:
• Hepatosplenomegaly
Patient with Acute Promyeloblastic
• Lymphadenopathy Leukaemia (APML) can present with
• Leukaemic meningitis excessive bleeding owing to primary
• Testicular Infiltration fibrinolysis and Disseminated
Intravascular Coagulation (DIC).
• Skin Nodules
Rx includes ATRA! (all-tran retinoic
acid)
 Acute Lymphoblastic Leukaemia
• ALL is the commonest cancer in children (23% of all cancers in
under 15 yr olds)
– 80% leukaemia free survival rate at 5 years
• Adult ALL does less well with only 30-50% long term survivors
Management
• Treated according to risk:
– Poor prognosis:
• Diagnosis <1yr or >9yrs, High white cell count (>50x109), male, Hypodiploidy (<45 chr), Genetics – Philadelphia
translocation or rearrangement of MLL gene, a higher level of Minimal Residual Dx.

• Chemo
– Induction of Remission
• Vincristine, Prednisilone & L-asparaginase (+/- anthracyline in high risk)
– Intensification
• New Drugs – cyclophosphamide, Cytosine Arabinoside, thioguanine.
• Clearance of CNS as a sanctuary – intrathecal methotrexate or irradiation
– Maintenance
• Methotrxate, Thiogunine, Vincristine, Prednislone & intrathecal prophylaxis
 Acute Myeloid Leukaemia
•Patient
Treatment depends
with Acute Promyeloblastic on
Leukaemiathe pts
(APML) canage and
present the
with excessive
bleeding owing to primary fibrinolysis and Disseminated Intravascular Coagulation (DIC).
performance score
This is a separate entity having FAB-M3 morphology and t(15;17) creating the PML-RAR
fusion gene,

• Chemotherapy
Rx includes ATRA! (all-tran retinoic acid)
This needs additional chemo to is essential to eliminate the leukaemic clone.
– ANTHRACYCLINE + CYTOSINE ARABINOSIDE
(ARA-C) given over 7-10 days has been the
backbone of Rx for 30 years
– The addition of a third drug (thioguanine or etoposide)
is widely used.
– “Successful induction” = <5% blasts

• Stem Cell Transplant

– Pts >60 are usually given intensive Rx with stem cell
transplantation
 AML – Prognostic Factors
• Good Prognosis
– t(8;21), t(15:17), inv (16)
• Bad Prognosis
– Chr 5, Chr 7, Trisomy 8
– High WBC at presentation
– P-glycoprotein overexpression
• Intermediate Risk
– None of the above
 Chronic Myeloid Leukaemia
• Epidemiology
– Can occur in either sex at any age
– Most commonly presents 40-60years
– There is an association with radiation
• e.g atomic bomb survivors
• Pathology
– CML is a malignancy arising from a multinucleated haemopoietic
pleuripotential stem cell
– In CML a clone of cells replaces the bone marrow with enhanced
proliferative capacity, but unlike in acute leukaemias these cells retain
the ability to differentiate during the chronic phase of disease
– Almost all have a Philidelphia Chromosome t(9;22) which causes
formation of a BCR-ABL fusion gene which translates into an abnormal
tyrosine kinase. This tyrosine kinase has been targeted by the new
therapeutic agent…
Imatinib (Gleevec)
– The disease runs a chronic phase for many years. In those that are not
cured by stem cell transplant, the cell eventually lose their ability to
differentiate and enter “Blast Crisis”, resembling an acute leukaemia of
myeloid or less frequently lymphoid origin (i.e. CML  AML), which is
fatal
 Chronic Myeloid Leukaemia
• Clinical Features
– Chronic phase:
• Anaemia, Weightloss, “Massive Splenomegaly”
• Can develop Gout
• Rarely altered consciousness, blurred vision and cardiorespiratory
failure can occur due to hyperviscocity with a very high white cell
count
• Investigations
– FBC
• Leucocytosis is a uniform feature and white cell count can be in
excess of 300x109/L. A normochromic anaemia is normally present
whilst platelets are commonly increased (sometimes >1000)
– Blood Film
• Resembles a bone marrow aspirate with all stages of myeloid
differentiation
– Bone marrow
• Hypercellular with predominant granulocytopoiesis. In blast crisis
increased number of blast cells
– Cytogenetics
• 95% have philidelphia chromosome (t(9;22) on routine G-banding
 Chronic Myeloid Leukaemia
• Management
– Chronic Phase
• Allogenic stem cell transplant
– Potential cure for CML
» Relapse rates usually less than 20%
» Cured patients have no Abl-Bcr by PCR which is the bench
mark for other treatments
– Transplant related mortality ranges from 15-40% (ouch)

• Imatinib (Gleevec)
– Standard therapy in all CML patients unable to have Allogenic
Stem Cell Transplant.
– It binds to the ATP binding site of BCR_ABL and inhibits the
function of the tyrosine kinase
– Complete haematological responses are achieved in 95%
– A minority develop resistance to Imatinib
– Doubles predicted survival to >10 years
 Myelodysplastic Syndromes
• MDS are a group of neoplastic disorders of bone
marrow characterised by dyplastic haemopoiesis
and peripheral blood cytopenias
• As part of the family of myeloid neoplasms, there
is a tendency to progress to acute myeloid
leukaemia.
• <20% of the nucleated cells in the bone marrow
are blast cells (otherwise it is leukaemia).
• Rx
– Supportive
• blood and platelet transfusions (+ iron chelation)
• EPO and G-CSF
– Allogenic Stem Cell Transplant
 Chronic Lymphoid Leukaemia
• Commonest leukaemia in western world!
– Account for 30-40% of all adult leukaemia in Europe.
• Accumulation of lymphoid cells in the peripheral blood
– These constitutively express Bcl-2 inhibiting apoptosis
• Epidemiology
– Occurs predominantly in late middle age and old age
– Median age 65-70 yrs
– Male:Female = 2:1
– Genetics may play a role
• Low risk in Japanese even after migration
• Classified by WHO criteria by morphology, surface
immunophenotype, cytogenetics and molecular biology.
• Some lymphomas may present bone marrow infiltration
 Chronic Lymphoid Leukaemia
• Laboratory features in CLL
– Lymphocytosis >5
– Normochromic normocytic anaemia +/- autoimmune
haemolytic anaemia (coombes)
– Thrombocytopaenia
– Hypogammaglobulinaemia
– Mature lymphocytosis with smear cells on blood film
– Diagnosis made on immunophenotype and
characteristic blood film
• Staging
– BINET CLASSIFICATION
• A (best), B, C (worst)
• Based on Hb, Platelets and organ enlargement
 Chronic Lymphoid Leukaemia
• Clinical Presentation
– Painless lymphadenopathy (symmetrical and generalised),
anaemia or infection e.g. shingles
– Splenomegaly in 66% at presentation & sometime hepatomegaly
– Indolent clinical course
– 80% are assymptomatic - diagnosed early after routine blood
count.
– Constitutional symptoms are restricted to patients with advanced
disease including, night sweats, fatigue an weight loss. In
advanced disease there is bone marrow infiltration with variable
degrees of anaemia, thrombocytopaenia and neutropenia.
• Other features that some get include
– Positive coombes test (Autoimmune Haemolytic Anaemia)
– Idiopathic Thrombocytopaenic Purpura
 Chronic Lymphoid Leukaemia
• Prognosis
– Good Prognostic Factors
• 13q14 deletion/ translocation
• Hypermutated Ig genes  25 yr survival
– Bad Prognostic Factors
• Lymphocyte doubling time (<12 months)
• Prolymphocytes (>10%)
• Trisomy 12
• Unmutated Ig genes  8 year survival
• 11q23 deletion
• p53 mutation
 Chronic Lymphoid Leukaemia
• Management
– Watchful waiting
– Systemic therapy is only indicated in symptomatic and advanced
disease.
• First Line
– Fludarabine (purine analgue)
– Chlorambucil (alkylating agent)
• Second Line
– Chlorambucil again
– CHOP (a combination therapy)
– Alemtuzumab (anti-CD52 antibody) in fludarabine failed CLL
– Radiotherapy – for LNs compromising vital organ function
– Splenectomy (in those with spleomegaly, anaemia or
thrombocytopaenia owing to hyperspnism)
» Prior to splenectomy patients require pneumococcal,
memingococcal and haemophilus vaccinaoin. Following
splenectomy life long prophylactic penecillin needs to be taken
• Autoimmune complications are treated with Steroids
 Lymphomas
• Neoplasia of the lymphocytes (B cells, T cells or
natural killer cells)

• Most common “blood cancers”

• New thrapies
– Rituximab – monclonal antibody based

• Classification
– HODGKIN’S LYMPHOMA
– NON-HODGKIN’S LYMPHOMA
 Hodgkin’s Lymphoma
• Incidence
– Large peak – 20-30
– Smaller peak – old age

• Aetiology
– Unknown but there has been associations with higher socio-
economic class, caucasian race (whites) and previous
clinical/severe glandular fever (EBV)
– HLA-DPB1
– An association with Epstein Barr Virus is well documented
• It occurs in around 30% of patients; especially mixed cellularity HL
and lymphocyte depleted HL in older patients.

• Pathology
– Pathognomic binucleate REED STERNBERG CELL
• This is the malignant cell in HL and recent studies have confirmed
its B cell lineage
 Hodgkin’s Lymphoma
• WHO classification
– Nodular Sclerosis Classical HL (~50%)
– Mixed Cellularity Classical HL (30-40%)
– Lymphocyte Rich Classical HL
– Lymphocyte Depleted Classical HL

– Nodular Lymphocyte Predominant HL

– A distinct entity, characterized by “L&H Hodgkins Cells” also known as
popcorn cells, which are of B cell lineage and express CD20.
Approximately 10% of NLPHL develop into diffuse large B-cell NHL.
This subtype has a favourable prognosis, though it might run a
chronically relapsing and remitting course over many years akin to low
grade NHL.
 Hodgkin’s Lymphoma
Presentation
– Painless rubbery lymphadenopathy (cervical LNs especially)
– May be generalized lymphadenopathy
– Later spread to liver, lung, marrow
– “B” symptoms
• Fever >38
• Night Sweats (drenching)
• Weight Loss >10% over 6 months
– Other systemic symptoms
• Itch
• Alcohol-induced pain in lymph nodes

Diagnosis
• Lymph node or tissue biopsy
• FNA can be suggestive but should not be used alone for diagnosis
 Hodgkin’s Lymphoma
Ann Arbor Staging System
I. – Single LN region
II.– Two or more regions on one side of the diaphragm
III – Two or more regions either side of the diaphragm
IV – Diffuse or disseminated disease in extra-lymphatic
sites including liver and bone marrow
• A = no systemic symptoms
• B = Systemic Symptoms Present
• E = Extranodal Diseasqe

PET scanning is useful in identifying active HL within

residual enlarged LNs.
 Hodgkin’s Lymphoma
Management of HL
• Since there are high cure rates and it generally affects
young adults, potential long term toxicities of therapies
become of major importance
– Twice as many patients have died from secondary cancers than
of relapsed HL
– Mantle radiotherapy was associated with 1 in 3 secondary breast
ca risk by 50 yrs of age
– Alkylating agent based chemo is associated with secondary
myelodysplasia, AML and NHL and infertility
– The recognition of the long-term toxicity of radiation therapy,
particularly to the mediastinum (secondary cancers of the lung,
breast, pulmonary fibrosis, coronary artery disease) has led to
major re-evaluation of the use of extensive radiotherapy
 Hodgkin’s Lymphoma
Management of HL
• Early Stage (IA and IIA)
– Very good prognosis  involved field radiotherapy alone
– Good prognosis (most)  2-4 course of ABVD (adriamycin,
bleomycin, Vinblastine, dacarbazine) followed by involved field
(IF) radiotherapy
• Advanced Stage
– Doxorubicin-based chemo, particularly ABVD, is the most widely
for advanced HL.
– Other regimes include BEACOPP
• Salvage Therapy
– Patients who relapse after radiotherapy generally have good
response to subsequent first line chemo (80-90% get DFS)
– Patients who relapse after chemotherapy generally have good
response to subsequent second-line chemo but only 20-25%
achieve long-term DFS.
– High-dose therapy and Autologous Stem Cell Transplant (ASCT)
can produce superior long-term DFS (DFS in 40-50%)
 Non-Hodgkin’s Lymphoma
• Arise from lymphocytes and their precursors
• No reed sternberg cells
• NHL is increasing in frequency
• Incidence increases with age (median 5-60years)
• Tumour Marker = LDH
• Pathogenesis is unclear but aetiological factors include
– Longevity
– Prolonged immunosuppression
– Epstein Barr Virus (EBV)
– Helicobacter gut infection
– Chlamydia infections in Occular Margin Zone Lympohomas
– Hep C in Marginal Zone Lymphomas
– Regular use of hair dyes
 Non-Hodgkin’s Lymphoma
• Classification
– Immunological identification of lymphocytes and
molecular analysis of immunoglobulin and T-cell
receptor gene rearrangements have allowed
improved classification of NHL based on the biology
of cells rather than just morphological description.
– The majority of NHL are B-cell type
– WHO classification
• Based on B-cell / T-cell lineage, its origin and whether
pathologists can reproducibly identify it as a distinct entity
– Treatment is based on grade rather than
classification.
 Clinical Features of NHL
• The majority of adults patients (60%) present with nodal
disease, whereas the majority of children present with
extranodal disease.
• Hepatosplenomegaly is common and extranodal sites
include the gut, testes, thyroid gland, bone, muscle, lung,
CNS, facial sinuses and skin.
• Systemic features include
– Drenching night sweats
– Loss of weight (>10% in 6 months)
– Culture-negative fever >38
• Medical Emergencies in NHL include
– Mediastinal obstruction
– Obstructive Nephropathy
– Spinal Cord Compression
– Hypercalcaemia and Metabolic Derangements
• Ascites and pleural effusions are common end-stage
features, especially in high-grade NHL.
 Low-Grade NHL
• Low grade lymphomas comprise 20-45% of NHL. They tend to be
dissseminated at the time of diagnosis, with widespread lymphadenopathy,
hepatosplenomegaly and ,often, blood and marrow involvement.

• Follicular Lymphoma (FL)

– This is the archetypal low-grade NHL and the most common subtype of indolent
(low-grade) NHL (30% of cases).
– Most commonly presents in stage II or IV when it is incurable, but runs a
relapsing and remitting course with median survival of 6-10 years
– Caused by a translocation causing up-regulation of Bcl-2 protecting the
lymphoma cell from apoptosis

• Management Strategies
– Stage I – Involved Field Radiotherapy
– > Stage 1 – No chemo until significant symptoms
– Significant Symptoms
 R-CVP (R- Cyclophsophamide, Vincristine, Pred)
 R-CHOP (Rituximab, Cyclophosphamide,
Hydroxydaunorubicin, vincristine and
Prednisilone)
 Low-Grade NHL
• Treatment at time of progression from first
response include
– Purine analogues: fludarabine and 2-CDA
– Autologous / allogenic stem cell transplantation
– Radiolabelled anti-CD20
– Alpha interferon
– Rituximab

• Prognosis
– Follicular Lymphoma Prognostic Index (FLIPI)
– Includes information on age, stage, haemoglobin, LDL and no
of nodal sites
– Gene expression profiling
 High Grade NHL
• High grade NHLs best regarded as those with a
propensity to invade the CNS
– Lymphoblastic, Burkitt’s, ATLL, primary CNS lymphoma (PCL)
– Treatment can be curative
• Burkitt’s Lymphoma
– Endemic
• Endemic in equatorial africa
• 90% associated with EBV infection
• Young adults /children present with head/neck tumours
– Non-Endemic
• NHL associated with EBV ~20%
• Abdo dx more common
• Associated with HIV
– Management:
• Short intensive chemo with methotrexate , cyclophosphamide and
ifosamide, with intrathecal therapy. The regime CODOX-M alone for
low risk disease (early stage and normal LDH). CODOX-M
alternating with IVAC for poor risk disease.
 High Grade NHL
• Lymphoblastic Lymphoma
– Presents with or without leukemia, is more common in children than
adults and is more often T-cell type, typically featuring a mediastinal
mass and pleural effusion
– Treatment includes emergency management of mediastinal obstruction
and prevention of tumour lysis syndrome
– Poor prognostic features include bone marrow &/or CNS involvement,
LDH > 300IU/L, Age>30. Allogenic and autogenic stem cell transplant
may improve survival in these cases

• Diffuse Large B cell NHL (DLBL)

– Commonest high grade NHL.
– Radiotherapy alone or more commonly short course CHOP-like chemo
followed by involved field radiotherapy can cure ~90% of the non-bulky
stage IA dx.
– Other stages  R-CHOP
– Relapsed DLBL
• High-dose salvage chemo & autologous stem cell transplant
– Prognosis
• International Prognostic Index & gene expression profiling
 Lymphoplasmacytoid Lymphoma
= Waldenstroms Macroglobulinaemia
• Cancer of lymphocytes which shares attributes with
indolent Non-Hodgkin’s Lymphoma.
• A distinguishing feature of WM is the presence of an IgM
monoclonal protein
• Symptoms include
– Weakness, fatigue, wt loss and chronic oozing of blood from the
nose and gums.
– IgM can cause autoimmune phenomena or cryoglobulinaemia
 Myeloma
• Monoclonal expansion of plasma cells
• 60% myeloma produce IgG, 20% IgA and
20% free light chain
– Basically NO IgM
• Disease of OLD AGE
– Median age ~70yrs
• Treatment is not normally curative
• Poor prognosis cf. Waldenstroms
Macroglobulinaemia
• Median survival ~3 - 5 years
 Myeloma
• Pathology
– Plasma cell dyscrasias can present in a number of ways
• MGUS (Monoclonal Gammopathy of Uncertain Significance)
– Serum paraprotein <30g/L, bone marrow clonal cells <10% and no
features of myeloma-related organ or tissue impairment
(hypercalcaemia, bone lesions, renal impairment, anaemia,
symptomatic hyperviscocity, amyloidosis, recurrent bacterial infections)
– Prevalence is 20x that of multiple myeloma!
– 1% progress to MM each year
• Solitary plasmacytoma (either bone or extramedullary)
– Spinal Cord Compression
– Myeloma develops in 2/3rds
• Smouldering / asymptomatic Myeloma
– >10% clonal plasma cells in bone marrow & serum paraprotein >30g/L
• Multiple Myeloma
– Light chains can pass through the glomerular filter and appear in the
urine as Bence Jones protein
 Myeloma
• Features:
– Bone Reabsorption
 Bone Pain + Hypercalcaemia
• Lytic lesions
– This is due to increased levels of RANK protein produced by Myeloma cells and
suppression of osteopetegrin (OPG)
• Osteoporosis
• Fractures
– Marrow Infiltration
 Anaemia / Fatigue
– Paraprotein (M protein)
 Renal Failure (may need dialysis) + Hyperviscocity
• Light chain (antibody) protein deposited in kidneys
• High calcium
• Dehydration
 Myeloma Diagnosis
• Investigations
– FBC
– ESR/plasma viscocity
– U&Es and serum calcium and albumin
– Electrophoresis and immunofixation of serum and urine for
paraprotein
– B2 microglobulin  prognosis (lower = better)
– Bone marrow aspirate or trephine
– Skeletal Survey

• Generally a triad of
– Bone marrow infiltration with monoclonal plasma cells
• Bone Marrow aspirate / trephine
– Osteolytic lesions on skeletal survey
– Paraproteinaemia / Bence Jones Protein
 Management of Myeloma
• Untreated death normally results within months (infection
& renal failure) and is often preceded by intractable bone
pain.
• Initial therapy should include:
– Adequate analgesia (opiates & local RT)
– Rehydration and vigorous rx of hypercalcaemia (IV bisphosphonate)
– Dialysis is occasionally required for Renal Impairment
• Chemo
– Melphalan +/ - Pred
• or Cyclophosphamide or dexamethasone until plateau phase
– Occasionally some younger pts will have stronger chemo
(VAD/cVAMP) before autologous stem cell reinfusion & G-CSF
• Newer Agents
– Thalidomide
– Bortezomib
 Prostate Cancer
• Aetiology
– Uncommon in Japanese and Indians
– More common in AFRICANS
– Growing number – aging population
• Incidence
– 15% of 50 yr olds have islands of ca in their prostate
– 1st most common cancer in males
• Pathology
– 95% adenocarcinoma
– Cancer usually (70%) arises from the outer zones
– If ca arises from the inner zones it seldom spread and behaves
as if benign
– Androgen - dependant
– Prostate Interstitial Neoplasia (PIN) is the precursor to prostate
cancer
– 5% genetic – including BRCA1 & 2
 Prostate cancer
• Locally advanced Symptoms
– Prostatism
• Prostatism is compression of the urethra causing symptoms
synonymous with BPH
– Frequency, nocturia, poor stream, retention, haematuria.
– Rectal Obstruction
• Rectal obstruction can cause pencil thin stools and progressive
constipation
– Uraemia
• Ureteric obstruction can lead to hydroureter and hydronephrosis and
uraemia

• LN mets  lymphoedema in the legs and genitals

• Bone Mets  bone pain / # / spinal cord compression

• Symptoms may be scored with the International Prostate

Symptoms Score (IPSS)
 Prostate cancer
• Distant Metastases
– Usually to the BONES
• Often involve lumbar vertebrae, pelvis and femora
• Cause bone pain, pathological fracture or spinal
cord compression
• Typically denser than bone ie. Osteoblastic
(sclerotic)
 Prostate cancer
Gleason Grading
• Based on the assessment of the pattern of
growth seen in two different sites of the prostate
• 1 to 5 with 5 being the highest grade and
carrying the poorest prognosis. A pathologist
determines Gleason grades by analysing
histology from two separate areas of tumour
specimen and adding them to get the total from
2 to 10.
– 8 - 10 = aggressive
–5-7 = intermediate
–2-4 = indolent
 TNM Staging
• T stage
– Assessed by DRE and imaging (TRUS, MRI)
– T1 – not palpable
– T2 – palpable on DRE
}
Watchful waiting but Treatable with RT/surgery
(NB: 40% of palpable nodules are malignant)
– T3 –Extracapsular
– T4 – Palpable and fixed (invading) to surrounding tissue
• N stage
– N0 or N1
• M stage
– M1a – non-regional LN mets
– M1b – Bone mets
– M1c – Mets in other sites
 Investigations for Prostate Cancer
• Transrectal Ultrasound (TRUS)
– TRUS with guided biopsies are the most common
diagnostic modality for prostate cancer.
– Provides imaging of the prostate & seminal vesicles
– The echogenicity of the prostate is determined by the
amount of calcium in the tissues, which in cancer may
be greater or lesser than normal
– Hyper/hypo-echoic regions in the peripheral zone may
also be due to inflammation.
– BIOPSY carry a 1% risk of sepsis or significant
bleeding!!!
• Up to 4 biopsies are taken from each lobe with antibiotic
cover
• For staging you need
– CT, MRI & CXR
 Mechanisms of Androgen Deprivation
All used in Metastatic Disease
• Surgical Castration
– Bilateral orchidectomy
– Impotence, loss of libido, fatigue, mood disturbance and muscle
weakness
• Medical Castration
– LHRH analogues
• E.g. Goserelin
• Causes initial flare with rise in testosterone then fall to castration levels –
requires anti-androgen cover for first two weeks
• Anti-androgens
– Androgen receptor blockade at target cell
– Steroidal
• Cyproterone acetate
– Non-steroidal
• Bicaltumide or flutamide
• Maximal Androgen Blockade (MAB)
– Medical or surgical castration + antiandrogen
• 5-a- Reductase Inhibition
– Finasteride or dutasteride
 Treatment for Prostate Cancer
1. Watchful Waiting
2. Radical Prostatectomy
3. Radical External Beam Radiotherapy
(EBRT)
4. Brachytherapy
5. Hormone Therapy
6. Cryotherapy & HIFU
7. Palliative
 1 Watchful Waiting
• Best option for patients with localized prostate
cancer and:
– Gleason score 2-4
– Gleason 5-6 & >75 years
– Significant Comorbidity  life expectancy <10 years
– Stage T1a with normal PSA

• Seen every 6 months for clinical history,

examination (including DRE) and a serum PSA
test.
 2 Radical Prostatectomy
• RP is excision of the entire prostate, including
the prostatic urethra with the seminal vesicles
• Can be performed open retropubic, perineal or
laproscopic
• Following excision of the prostate there is
reconstruciton of the bladder neck and vesico-
urethral anastamosis
• Indicated in fit men with localized prostate
cancer whose life expectancy is >10 years
3 Radical External Beam Radiotherapy
(EBRT)
• EBRT is radiotherapy with linear accelerators
(conformal & intensity – modulated techniques to
minimise toxicity to the rectum and bladder)
• EBRT is administered with curative intent and
often accompanied by 3 months neo-adjuvant
hormone therapy in high risk cases
• Indicated if:
– Localized Prostate Ca
– Life expectancy >5 years
 4 Brachytherapy
• This is ultrasound guided transperineal
implantation of radioactive seeds, usually I125into
the prostate
• It may be augmented with an EBRT boost

• BT is indicated if
– Localized T1-2
– Gleason >7
– PSA <10ng/ml prostate ca
– Life expectancy >5 years
• Cryotherapy & High-Intensity Focused
Ultrasound
– Cryotherapy and HIFU are in development
and claim to be viable alternatives to surgery
or radiotherapy
 5 Hormone Therapy
• Hormone Therapy with or without EBRT is used
to treat locally advanced non-metastatic disease
(T3-4 N0M0)
• Non-steroidal anti-androgens (e.g flutamide or
bicaltumide) has equivalent efficacy to androgen
deprivation by orchidectomy or LH-RH analogue
• Hormone therapy is NOT a treatment initiated
with curative intent

• It is also used to treat advanced prostate ca

– Mainstay of treatment is HT with Cytotoxic
chemotherapy in reserve
 Hormone Therapy
• 95% of circulating androgen (mainly testosterone) is produced by
the Leydig Cells of the testis under the influence of Lutenizing
Hormone (LH)
• The Ant. Pituitary synthesizes LH stimulated by LH-releasing
hormone (LHRH) produced by the hypothalamus
• The remaining 5% of androgen is produced by the adrenal cortex
from cholesterol under the influence of ACTH
• Testosterone is metabolised to the more potent Dihydrotestosterone
(DHT) by types 1&2 5-α reductase (5AR) enzymes
• DHT binds to the androgen receptor, travels to the cell nucleus &
exerts its positive effect on cell growth & cell division
• All prostatic Epithelial cells are dependent on androgens and fail to
grow in their absence. Similarly most prostate ca cells are
dependent on androgens
• Androgen deprivation results in clinical improvement in 70% but
most will still die within 5 years
 Hormone Resistant Prostate Cancer
(HRPC)
• Poor prognosis

• Treatment Options:
– Palliative Chemotherpy
• Docetaxel
– Strontium- Zoledronic Acid
• In boney mets
 PSA
• When to do it:
– Afrocarribean
– Symptomatic
• LUTS
• Haemospermia (?invasion into seminal vesicles)
• Bone Pain
– Family History
– Do it again if first one is abnormal!!! (Need two)
– Repeat if very high – exclude infection

• When NOT to do it:

– Patients <40 years
– UTI (treat this first)
– Elderly - asymptomatic + comorbidities meaning <10 yr life
expectancy
 PSA
Urology Referral Thresholds (95% Confidence
Intervals)

• <50 yrs  2.5

• 50-59  3.5
• 60-69  4.5
• 70-79  6.5

• Over 80 yrs are generally not candidates for

radical rx; progression rarely occurs unless PSA
>15
 Role of Surgery in GYNAE CA
• Diagnosis
• Biopsy of the cervix, vagina and vulva is generally very easy to achieve
• Endometrial Cancer diagnosis is slightly more problematic:
– The endometrium or uterine lining cannot be directly visualised so to biopsy it
you need to use suction curettes or hysteroscopy
– The “Pipelle” is small enough to enter through the cervical canal and through
suction can harvest endometrial tissue.
– Hysteroscopy – a small telescope is passed through the endocervical canal with
fibreoptic lighting and partial distension of the uterine cavity by either saline or
gas once can visualise the endometrial cavity and take direct biopsies. Most are
done under GA due to the need to dilate the cervix which can be uncomfortable.
Some are done as outpatient.
– Ultrasound is useful as a first line for women presenting with symptoms of
endometrial cancer as it allows the measurement of endometrial thickness (If
>5mm in postmenopausal woman  biopsy):
• POST MENOPAUSAL BLEEDING
– Other interesting features on USS include a fluid filled cavity, irregularities in the
endometrial lining that might indicate polyps or neoplasia. Both of these also
necessitate further assessment of the endometrial cavity.
• Intra-abdominal disease
– Ovarian cancer often presents quite late – most in
stage 3 or 4 (once spread well beyond the ovary)
largely because the early stages are not associated
with any specific symptoms.
– Can present with ascites  cytology
– O/E multiple masses within the abdomen – “omental
cake”  image guided biopsy (CT /USS)
– If not possible to confirm malignancy and
histiogenesis, then as a last resort, one might perform
a Laparotomy. This is primarily to biopsy to
suspicious tissue but also to remove as much of it as
possible, which improves subsequent response to
chemo.
– Other tumours can through metastases into the
abdomen: carcinoma of the stomach, bowel,
pancreas, gallbladder and breast. Krukenberg mets.
 Staging
In gynaelogical cancer staging is devised and maintained
by FIGO (Federation International for Gynaecology and
Obstertrics).

• Clinical staging
– Doesn’t take into account the findings of any surgical procedure
e.g. if a stage 1b cervical cancer on undergoing radical
hysterectomy was found to have LN involvement, it’s stage
would remain 1b and not be upstaged to stage 3.

• Surgical Staging
– Does include information found on surgical and information from
subsequent pathological biopsies.
Cervical Cancer Staging
• Cervical cancer is clinically staged. The clinician should be able to see if the cervix is abnormal but by bimanual
examination should be able to determine if there is spread into the parametrium or upper parts of the vagina.
• Often requires a concurrent bimanual rectal and vaginal examination, to determine involvement of the
endometrium
• Staging does not require the removal of any tissues such as LNs.
– Stage 1a – microscopic – only seen histologically
– Stage 1b – macroscopic – seen clinically but confined to cervix
• 1b1 <2cm
• 1b2 >2cm <4cm
• These are technically amenable to surgery. In practice large tumours are often considered for radiotherapy or
chemo-radiation
• Generally there is a consensus that we should avoid radiation in women who have undergone serious abdominal
surgery e.g. radical hysterectomy as an a result has been found to have incomplete excision margins or involved
lymph glands  risk of relapse is high so adjuvant radiotherapy would be beneficial; BUT the morbidity and
mortality from radiotherapy after surgery is awful. The thinking goes then, that if you think the need for post-op
radiation is high then one should consider giving radiotherapy as the primary treatment
– Stage II – spread beyond the cervix
• IIa – upper third of vagina
• These are potentially considered amenable to surgical removal
• IIb – Parametrium
• Surgery is not considered!
• Note that the ureters pass by close to the border of the cervix in the parametrial tissues  in advanced cervical
cancer compromise of the ureter is not uncommon.
• Staging involves an IV Urogram to determine if there is any involvement of the ureters (hydroureter /
hydronephros / non-functioning kidney). If any ureteric compression is there then the ca is upstaged to Stage 3b
– Stage III
• IIIa – beyond the upper third of the vagina (downwards), but no extension to pelvic sidewall
• IIIb – palpable tumour extends to pelvic side wall / evidence of ureteric involvement
– Stage IV
• IVa – spread to adjacent organs  bladder or rectum
• IVb – spread to distant organs
• It is often asked why in Cervical Cancer LNs are not included in the staging of the disease when LN status is
an important determinant of the outcome of this disease. The answer: The majority of Cervical Ca is managed by
External Beam Radiotherapy (EBRT) +/- chemo, as most present at a stage when they are not amenable to
surgical rx. If people are going to be treated without surgery, then you can’t remove their LNs, so this shouldn’t
contribute to the staging process.
• If the cancer is amenable to surgery, the LN status will be detected at surgery. If nodes are involved the patient
requires radiotherapy, but the stage remains the same.
TAH = Tissue Hysterectomy BSO = bilateral ovary removal
Lymph Node Sampling
Spread of disease to local lymph nodes is primarily a prognostic indicator
but also in making decisions on treatment.

Vulval Cancer
• Groin (Femoral) Nodes
• Block dissection of Inguinal LNs with tumour or LN sampling. If positive –
post-op radiotherapy reduces recurrence and improves survival
• NB: Wound breakdown is common after surgery for vulval ca.

Endometrial Cancer
• Pelvic Lymph node removal has shown no improvement in overall surgical.
However, LN sampling is still a part of FIGO staging.

Ovarian Cancer
• Para-aortic LNs – If in stage I dx, if no evidence of any (even microscopic)
spread then you could avoid chemotherapy. However, if there is ample
evidence of extra-ovarian cancer, there would be no reason to sample the
LNs as treatment is the same!
• NB: Prior to ovarian ca surgery you may well take tumour markers CA125.
In younger patients bHCG & AFP will be taken as younger patients are
much more likely to have a germ cell tumours which secrete these tumour
markers.
Surgery

Ovarian cancer
• Laparotomy is the operation of choice for diagnosis and staging and
excision tumour. Gold standard is to remove all visible ca but this is not
often possible as most present with widespread mesenteric / peritoneal
mets  “Tumour debulking” (try to reduce residual disease so no disease
left has a diameter over a certain size. eg. 2cm. With less volume perhaps
chemo is more effective.
• Used for Palliation
• Stage I/II – surgery is seen as a cure
• More advanced stage – adjuvant chemo is almost always required

Cervical cancer
• No evidence surgery is better than radiotherapy.
• Wertheims Hysterectomy – up to stage IIa
– remove uterus, parametrium, cervix and upper 1/3rd of vagina
– almost always performed with bilateral pelvic lymphadenectomy (removal of
internal and external iliac lymph nodes, obturator LNs and common iliac LNs)
– Preserves ovary function – radical radiotherapy would result in long term
hormone replacement
– Does take away reproductive capacity. This can be retained in a different
conservative operation.
– Adjuvant Radiotherapy is considered if LN involvement or poor tumour margins
Endometrial cancer
• Majority are early stage and surgery is considered superior to radiotherapy
• Uncertain role of pelvic lymphadenectomy - ?negative – sparing radiotherapy
• FIGO Staging requires LN sampling and peritoneal cytology
• If cancer has spread to cervix might perform Wertheims Hysterectomy

Vulval Carcinoma
• Radical surgery continues to be refined – becoming less and less radical to prevent the common
problems after surgery (wound infection / breakdown, Groin lymphocysts, Leg lymphoedema)
• Butterfly Incision  Triple Incision  Wide Local Excision
– if starkly unilateral don’t need to remove other side
– no need for vulvectomy in many cases
• En-bloc Radical Vulvectomy – groin LNs removed together with tumour.
• Tumour size, site, type and clinical suspicion of inguinal LN dx will determine the choice of
surgery.
• Sentinal Node Biopsy – inject technetium 99 to find LNs that drain the organ. Use a gamma
camera at operation to take out this/these nodes.
• Reconstruction
• Exenteration – super-radical surgery
• Total  removal of bladder, rectum, vagina [TAH, BSO]. Formation of Ileal Bladder Conduit and Colonostomy.
• Anterior  preservation of rectum
• Posterior  preservation of bladder
– The most common time when these would be considered is central pelvic reoccurrence of cervical
carcinoma.
– Careful patient selection - young
– 10% operative mortality
– Can achieve up to 50% 5 year survival
 Oesophageal Ca
Epidemiology
• M:F = 3:1
• Tumours for upper 1/3 – F>M
• Peak incidence: 60-70 years age
• Highest incidence in Russia, Turkey,
China, Iran, South Africa
 Aetiology
• Smoking
• Alcohol
• Barrett’s oesophagus
– Lower 1/3 metaplasia – sq. cell -> columnar
cell -> adenocarcinoma
– GORD
• Achalasia
• Patterson-Brown-Kelly syndrome
• Tylosis
 Clinical features
• Dysphagia • Weight loss
– Solids worse than • Malnourished
liquid
• Anaemia
• Regurgitation
• Retrosternal
discomfort
• Recurrent aspiration
 Investigations
• Barium swallow
• Endoscopy ***
– Biopsy
– Also evaluate stomach
• Bloods
– Alkaline phosphatase, gamma-glutamyltransferase
• CT thorax/abdomen Mets
-Liver
• Bronchoscopy -Bone
• CXR -Lungs
Investigations
 Management - radical
• SURGERY
• Lower 1/3 oesophagus
– Surgery Rx of choice
– Anastamosis
• Middle 1/3
– Ivor Lewis method
• Contraindications
– Poor performance status
– Vocal cord palsy
– Fistula
– LN involvement, Mets
• Operative mortality <5%
• RADIOTHERAPY
• Rx of choice for upper
1/3
• & anywhere else
where surgery not
possible
• Mortality lower than
surgery
• Neo-adjuvant chemo
– 5-FU
+cisplatin/mitomycin C
 Management - palliative
• E.g. controlling • Fibreoptic endoscopy
regurgitation, • Endoprosthesis
dysphagia
• Laser therapy
• Radiotherapy – Bleeding tumour
– External beam
radiation
– Intraluminal
brachytherapy
• Chemotherapy
– 5-FU + cisplatin
– ECF for
adenocarcinoma
 Prognosis
• Overall 5-year survival = 5-10%
• Usually due to occult LN/mets at
presentation

• Prevention?
– Stop smoking, reduce alcohol
– Barrett’s oesophagus
• Offered annual endoscopic examination
• Prophylactic resection
 Summary
• Older; men
• Predisposing conditions / aetiology
• Symptoms
• Investigations
• Management – radical & palliative
• Poor prognosis