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Oncology Revision Environmental Factors

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This document discusses environmental factors that can contribute to cancer development, including certain viruses, bacteria, parasites, diet, alcohol, smoking, oral contraceptive pills, and other carcinogens. It also summarizes common cancers among men and women, the prerequisites and considerations for effective cancer screening programs, examples of tumor markers used to detect different cancer types, an overview of the cell cycle and factors that regulate it, key oncogenes and tumor suppressor genes, methods to identify these genes, and aspects of signal transduction pathways involving growth factors, receptors, and the Ras pathway.

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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 1. Prostate 2. Lung 3. Colorectal Women 1. Breast 2. 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 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 Early stage forms of Ca • Cervix: – Cervical Intraepithelial Neoplasia (CIN) • Breast: – Ductal Carcinoma in Situ (DCIS) • Colorectal: – Adenomatous Polyps • Prostate: – Carcinoma In Situ – Prostate Interstitial Neoplasia
• Sensitivity – 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 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
• Cervical Screening – 3 yearly 25-49 – 5 yearly 50 years to 64 • 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 Test is acceptable Adequate facilities for diagnosis & rx Determine if repeat screening needed Benefits should outweigh risks Should be cost effective
Negative Aspects of Screening – False Negatives • 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 screening needed Benefits should outweigh risks Should be cost effective
• Cost per life – 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. 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 Should be cost effective
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)
Routine TMs• Ca 19-9 – 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  ERK 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 at the G1-S checkpoint a) Rb Cell cycle control b) MTS1 Cell cycle control c) BRCA 1 & 2 Transcription factors d) Oncogenes Ras Signal Transduction e) Myc Transcription Factor f) Erb-B / HER-2 Growth factor receptor g) Src Signal Transduction h) Breast, Lung, Colon, glioma, sarcoma Lung, breast, Cervix Retinoblastoma, Small cell lung cancer Osteosarcoma Glioma, melanoma, lung, bladder, mesothelioma Familial Breast and Ovarian Cancer Pancreas, Colon, Lung Breast, Lung, Stomach 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…. – Verification of treatment • E.g. Portal Imaging PET +CT)
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 • Allows for uncertainties in rx set- up: – Variations in pt positioning – Internal Organ Movement – Tolerances of machine calibration Multileaf Collimeters use 0.5cm leaves to shape the beam so RT is more focused It is also critical to define the position of critical organs - 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 – Sarcoma – Endometrial – Testicular Tumours – Rectal – ALL - Medulloblastoma - Small Cell Lung - “Involved Margins” - Thyroid (I131 ) - 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 – Pain – Bleeding • Lung; bladder; cervix; skin – Dysphagia – Neurological Symptoms • Brain / spinal cord – SVCO • Neoadjuvant RT – Rectal Cancer – Head and Neck • Uses in Benign Dx – Keloids (overgrown scars) – A/V Malformations – Acoustic Neuromas – Pituitary Adenomas – Cardiac Brachytherapy – 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 • Myelosupression  Commonest dose limiting side effect • Mucositis – Mouth Ulcers, Diarrhoea… – Secondary Infection – Common with 5 Flourouracil (CMF) • Toxic limiting factor with 5FU is mucositis Rx: Analgesia, Mouthwash Systemic + Topical Antifungal Slow gut transit - loperamide • Alopecia • Skin – red dry hands and feet Other Effects • Neurological – Platinum agents & Taxanes • Nausea & Vomiting (bodies protective mechanism) • Fatigue • Cardiac – Anthracyclins eg. Epirubicin • Renal – Platinum Agents (eg. Cisplatin) • Pulmonary – Bleomycin  Fibrosis • Allergy
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 (HERCEPTIN) Her-2 +ive Breast Ca erbB2 (HER2) 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 2nd trimester) • 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 a) b) Benign / Malignant c) d) More common? e) f) Spread via g) h) Pre-malignant phase? i) j) Age onset k) l) Epithelium Connective Tissue Always Malignant Always Malignant Common Rare Lymphatics Blood Yes No Older patients 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 • 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 more regional Lns Gastric Adenocarcinoma • pN0 No regional LN mets • pN1 Mets in 1 to 6 regional LNs • pN2 Mets in 7-15 regional LNs • 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
Aetiology• Age – V. Rare <20, Rare <30 – Incidence doubles every ten years until th menopause – After 50 the rate slows and in some countries plataues • 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 Male breast cancer may be associated with Kleinfelters Syndrome (47 XXY) Peak incidence is ten years later than in women
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 •Breast changes (telangiectasia, fibrosis, slow shinkage for 3-4 years) •Radiation Pneumonitis (responds well to steroids) •Osteoporosis / rib fracture •Second cancers (sarcoma) If irradiate the axilla: •Lymphoedema •Restricted Shoulder Movement •Brachial Plexopathy - Numbness, pain, weakness Early Hazards •Inconvenience •Tiredness •Breast swelling •Breast pain •Inframammary fold burn Current Research Fractionation Intraoperative Radiotherapy
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 Mets 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 • 1-3% 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 – Altered bowel habit – Blood and mucus per rectum – Abdominal pain • Right Colon – Anaemia – Mild diarrhoea – 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 OxaliplatinOxaliplatin • 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
Lung CancerPathology – 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) • 2nd line: (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 – Multidrug regimes • Limited stage disease – Thoracic Irradiation used concurrently with 1st or 2nd cycle of after chemotherapy if disease is responsive • Extensive Disease – Thoracic irradiation may be used if there is a good response to chemotherapy 4-6 cycles if disease is responsive Maintenance treatment is not recommended
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 • Primary Hyperparathyroidism • Medullary carcinoma of the Thyroid • Around 30% of MCT patients have germline RET mutations (chr10) • Phaeochromocytoma MEN-2b • Like MEN 2a but without parathyroid involvement and with mucosal neuromas (bumps on lips, tongue, cheeks and eyelids) and marfanoid appearance Pneumonic: Thyroid (Medullary Thyroid Carcinoma) Adrenal (Pheochromocytoma) Primary Hyperparathyroidism5
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 • Lymphadenopathy • Leukaemic meningitis • Testicular Infiltration • Skin Nodules Patient with Acute Promyeloblastic Leukaemia (APML) can present with excessive bleeding owing to primary fibrinolysis and Disseminated Intravascular Coagulation (DIC). 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 • Treatment depends on the pts age and the performance score • Chemotherapy – 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 Patient with Acute Promyeloblastic Leukaemia (APML) can present with excessive bleeding owing to primary fibrinolysis and Disseminated Intravascular Coagulation (DIC). This is a separate entity having FAB-M3 morphology and t(15;17) creating the PML-RAR fusion gene, Rx includes ATRA! (all-tran retinoic acid) This needs additional chemo to is essential to eliminate the leukaemic clone.
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
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Oncology Revision Environmental Factors

  • 2. 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
  • 3. 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)
  • 4. 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
  • 5. 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!
  • 6. 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
  • 7. OCP • Increases the risk of – Breast Ca – Cervical • Decreases the risk of – Ovarian Ca
  • 8.
  • 9. Most Common Cancers Men 1. Prostate 2. Lung 3. Colorectal Women 1. Breast 2. Colorectal 3. Lung
  • 10.
  • 11. 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
  • 12. 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 Early stage forms of Ca • Cervix: – Cervical Intraepithelial Neoplasia (CIN) • Breast: – Ductal Carcinoma in Situ (DCIS) • Colorectal: – Adenomatous Polyps • Prostate: – Carcinoma In Situ – Prostate Interstitial Neoplasia
  • 13. • Sensitivity – 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
  • 14. 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 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
  • 15. • Cervical Screening – 3 yearly 25-49 – 5 yearly 50 years to 64 • 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 Test is acceptable Adequate facilities for diagnosis & rx Determine if repeat screening needed Benefits should outweigh risks Should be cost effective
  • 16. Negative Aspects of Screening – False Negatives • 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 screening needed Benefits should outweigh risks Should be cost effective
  • 17. • Cost per life – 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. 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 Should be cost effective
  • 18. 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
  • 19.
  • 20. 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
  • 21. 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!!!
  • 22. 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
  • 23. 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)
  • 24. Routine TMs• Ca 19-9 – 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
  • 25. 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
  • 26. 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
  • 27. 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
  • 28. 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
  • 29. 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
  • 30. 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
  • 31.
  • 32. 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”)
  • 33. • 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
  • 34. 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
  • 35. 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
  • 36. 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
  • 37. 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.
  • 38. Signal Transduction RAS Signalling • RAS is an oncogene • There are many growth factors and their receptors that activate RAS • “Ras Raf  MEK  ERK 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
  • 39. 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
  • 40. 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 …
  • 41. 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
  • 42. 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
  • 43. 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.
  • 44. 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
  • 45. 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
  • 46. 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
  • 47. Gene Normal Function Associated Cancers Tumour Suppressor Gene p53 Regulates transcription at the G1-S checkpoint a) Rb Cell cycle control b) MTS1 Cell cycle control c) BRCA 1 & 2 Transcription factors d) Oncogenes Ras Signal Transduction e) Myc Transcription Factor f) Erb-B / HER-2 Growth factor receptor g) Src Signal Transduction h) Breast, Lung, Colon, glioma, sarcoma Lung, breast, Cervix Retinoblastoma, Small cell lung cancer Osteosarcoma Glioma, melanoma, lung, bladder, mesothelioma Familial Breast and Ovarian Cancer Pancreas, Colon, Lung Breast, Lung, Stomach Colon, Melanoma
  • 48. 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.
  • 49.
  • 50. Systemic cancer therapy • Includes. – Cytotoxic Agents – Immunomodulation – Targeted Treatments – Hormone Therapies – New age biological therapies
  • 51.
  • 52. 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
  • 53. • 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
  • 54. Norton Simon Hypothesis • Gompertiaz growth kinetics work both ways: – As tumours grow, the growth rate decreases – As tumour shrinks growth rate increases
  • 55. 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)
  • 56. 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…. – Verification of treatment • E.g. Portal Imaging PET +CT)
  • 57. 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 • Allows for uncertainties in rx set- up: – Variations in pt positioning – Internal Organ Movement – Tolerances of machine calibration Multileaf Collimeters use 0.5cm leaves to shape the beam so RT is more focused It is also critical to define the position of critical organs - Kidneys, Spinal Cord, Eyes
  • 58. 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
  • 59. 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
  • 60. 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
  • 61. 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
  • 62. 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
  • 63. Clinical Uses of RT The major use of RT in treatment is Adjuvant Treatment – Early breast ca – Sarcoma – Endometrial – Testicular Tumours – Rectal – ALL - Medulloblastoma - Small Cell Lung - “Involved Margins” - Thyroid (I131 ) - CNS
  • 64. Clinical Uses of RT Brachytherpy Needle insertion of radioactive seeds under GA Uses - Cervix - Prostate - Oesophagus (upper 1/3rd ) - Head and Neck
  • 65. Clinical Uses of RT • Palliation – Pain – Bleeding • Lung; bladder; cervix; skin – Dysphagia – Neurological Symptoms • Brain / spinal cord – SVCO • Neoadjuvant RT – Rectal Cancer – Head and Neck • Uses in Benign Dx – Keloids (overgrown scars) – A/V Malformations – Acoustic Neuromas – Pituitary Adenomas – Cardiac Brachytherapy – stents – Thyrotoxicosis
  • 66. 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
  • 67. 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
  • 68. 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
  • 69.
  • 70. 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
  • 71. Cytotoxic Agents and the Cell Cycle
  • 72.
  • 73. 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)
  • 74. 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.
  • 75. 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
  • 76. 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
  • 77. 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
  • 78. Common Chemotherapy Toxicities Effects on diving cells • Myelosupression  Commonest dose limiting side effect • Mucositis – Mouth Ulcers, Diarrhoea… – Secondary Infection – Common with 5 Flourouracil (CMF) • Toxic limiting factor with 5FU is mucositis Rx: Analgesia, Mouthwash Systemic + Topical Antifungal Slow gut transit - loperamide • Alopecia • Skin – red dry hands and feet Other Effects • Neurological – Platinum agents & Taxanes • Nausea & Vomiting (bodies protective mechanism) • Fatigue • Cardiac – Anthracyclins eg. Epirubicin • Renal – Platinum Agents (eg. Cisplatin) • Pulmonary – Bleomycin  Fibrosis • Allergy
  • 79. 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
  • 80. 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
  • 82. E-CMF • Breast Cancer • Epirubicin  Reversible heart damage • Cyclophosphamide • Methotrexate • Fluorouracil
  • 83. R-CHOP • Non-Hodgkin’s Lymphomas • Rituximab – Monoclonal Anti-CD20 • Cyclophosphamide • Hydroxydaunorubicin • Vincrisitne • Prednisilone
  • 84. ABVD • Hodgkin’s lymphoma • Doxorubicin (adriamycin) • Bleomycin • Vincristine • Dacarbazine
  • 85. BEP • Ovarian Cancer & Testicular • Bleomycin • Etoposide • Cisplatin (contain Platinum)
  • 86. MIC • Lung • Mitomycin • Ifosfamide • Cisplatin
  • 87.
  • 88. 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 (HERCEPTIN) Her-2 +ive Breast Ca erbB2 (HER2) erlotinib NSCLC (2nd line), Pancreatic Ca HER-1 / αEGFR Imatinib CML ATP receptor on BRC- ABL tyrosine kinase nimotuzumab SCCHN, Glioma EGFR
  • 89.
  • 90. Endocrine Therapy • Used in – Breast Ca – Prostate Ca – Carcinoid Tumours – Endometrial Ca – Ovarian Ca
  • 91. 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
  • 92. Aromatase Inhibitors • Irreversible – examestane • Reversible – anastrazole • Aromatase converts androgens to oestrogens
  • 93.
  • 94. 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
  • 95. 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
  • 96. 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
  • 97. 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
  • 98. 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
  • 99. 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
  • 100. 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
  • 101. 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
  • 102.
  • 103. 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
  • 104. 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
  • 105. 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
  • 106. 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
  • 107. 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
  • 108. 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
  • 109. SVO Obstruction • Pathophysiology – Pressure from tumour esp. apical lung – Direct Spread – Intraluminal thrombus • Causes – Carcinoma of the bronchus 65-80% – Lymphoma 2-10%
  • 110. 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
  • 111. Treatment of SVCO • Chemo (if chemo sensitive) • Radiotherapy • Stenting – Increasingly used 1st line
  • 112.
  • 113. Imaging in Oncology • Diagnosis • Staging • Assessing Response to Treatment • Diagnosis of Relapse • Evaluating the Complications – Primary disease – Treatment regimes
  • 114. 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!
  • 115. 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
  • 116. Staging Tumours • Cross Sectional Imaging – Ultrasound – CT – MRI – Positron Emission Tomography (PET)
  • 117. 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
  • 118. 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
  • 119. 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
  • 120. 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
  • 121. 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
  • 122. 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
  • 123. 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?
  • 124. 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
  • 125. 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 2nd trimester) • 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
  • 126. 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
  • 127. 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
  • 128. 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
  • 129.
  • 130. 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
  • 131. 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
  • 132. 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
  • 133. Carcinomas Vs Sarcoma CARCINOMA SARCOMA Derived from a) b) Benign / Malignant c) d) More common? e) f) Spread via g) h) Pre-malignant phase? i) j) Age onset k) l) Epithelium Connective Tissue Always Malignant Always Malignant Common Rare Lymphatics Blood Yes No Older patients Younger Patients
  • 134. 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
  • 135. 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
  • 136. Staging N • For regional lymph nodes found in the resection specimen • Stage varies depending on site / number of positive LNs Colorectal 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 more regional Lns Gastric Adenocarcinoma • pN0 No regional LN mets • pN1 Mets in 1 to 6 regional LNs • pN2 Mets in 7-15 regional LNs • pN3 Mets in 16 or more regional LNs *Ideally at least 15 nodes should be recovered from a gastric ca resection
  • 137. 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)
  • 138.
  • 139. 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
  • 140. 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
  • 141.
  • 142. 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
  • 143. 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”
  • 144. 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)
  • 145. 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.
  • 146. 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.
  • 147. 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
  • 148. 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.
  • 149. 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
  • 150.
  • 151. Breast Cancer • Incidence • Risk Factors • Screening • Diagnosis • Staging • Grading • Management
  • 152. 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
  • 153. Aetiology• Age – V. Rare <20, Rare <30 – Incidence doubles every ten years until th menopause – After 50 the rate slows and in some countries plataues • 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 Male breast cancer may be associated with Kleinfelters Syndrome (47 XXY) Peak incidence is ten years later than in women
  • 154. 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
  • 155. 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
  • 156. 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
  • 157. 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
  • 158. Prognostic Factors • Size • Grade • LN status! • Presence of vascular invasion • HER 2 +ive  worse prognosis
  • 159. 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
  • 160. 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
  • 161. 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
  • 162. 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)
  • 163. 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
  • 164. 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)
  • 165. 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)
  • 166. 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
  • 167. 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
  • 168. 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 •Breast changes (telangiectasia, fibrosis, slow shinkage for 3-4 years) •Radiation Pneumonitis (responds well to steroids) •Osteoporosis / rib fracture •Second cancers (sarcoma) If irradiate the axilla: •Lymphoedema •Restricted Shoulder Movement •Brachial Plexopathy - Numbness, pain, weakness Early Hazards •Inconvenience •Tiredness •Breast swelling •Breast pain •Inframammary fold burn Current Research Fractionation Intraoperative Radiotherapy
  • 169. 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
  • 170. 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
  • 171. 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)
  • 172. 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 Mets Palliative radiotherapy + Bisphosphonates
  • 173.
  • 174. 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
  • 175.
  • 176. 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.
  • 177. 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
  • 178. 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
  • 179. 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)
  • 180. 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.
  • 181. 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
  • 182. Hereditary Non-Polyposis Colorectal Cancer (HNPCC) • HNPCC = Lynch II Syndrome • 1-3% 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
  • 183. 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
  • 184. 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)
  • 185. 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
  • 186. 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
  • 187. Colorectal Cancer Symptoms • Left Colon – Altered bowel habit – Blood and mucus per rectum – Abdominal pain • Right Colon – Anaemia – Mild diarrhoea – Abdominal pain – Palpable mass • Rectum – Fresh bleeding – Mucus – Tenesmus – Pencil thin stools
  • 188. 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
  • 189. 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
  • 190. 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.
  • 191. 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
  • 192. Pattern of Spread • Local • Lymphatic • Vascular • Trancoelemic (rare) – Sister Mary Joseph Carcinoma – Ovarian transcoelemic spread often causes Krukenberg Tumours.
  • 193. 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
  • 194. 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
  • 195. 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
  • 196. 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
  • 197. Irinotecan • A topoisomerase inhibitor • Irinotecan Toxicity – Severe late onset diarrhoea – Neutropenia – Mucositis – Toxicity less used at lower dose in combination regimes OxaliplatinOxaliplatin • Causes intrastrand and interstrand crosslinks in DNA • Inhibits DNA synthesis and transcription
  • 198. 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
  • 199. 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
  • 200. 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
  • 201. • CEA – Raised  prognostically bad – Down than up  reoccurance • Most reoccurrences are detected by 2 years; nearly all by 5 years.
  • 202. Palliation • Palliative resection • Bypass • Stent – Usually for left sided unfit for surgery – Can perforate • Stoma
  • 203.
  • 204. 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
  • 205. 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
  • 206. Lung CancerPathology – 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)
  • 207. 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
  • 208. 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
  • 209. 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)
  • 210. 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
  • 211. 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.
  • 212. 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
  • 213. 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.
  • 214. 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) • 2nd line: (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
  • 215. Lung Ca - SCLC Rx of Small Cell Lung Cancer • All patients: – Platinum based chemo – Multidrug regimes • Limited stage disease – Thoracic Irradiation used concurrently with 1st or 2nd cycle of after chemotherapy if disease is responsive • Extensive Disease – Thoracic irradiation may be used if there is a good response to chemotherapy 4-6 cycles if disease is responsive Maintenance treatment is not recommended
  • 216.
  • 217. 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
  • 218. 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
  • 219. 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
  • 220.
  • 221. 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
  • 222. 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
  • 223. MEN-1 • Primary Hyperparathyroidism • Pituitary Tumours • Pancratic Neuroendocrine tumours MEN-2a • Primary Hyperparathyroidism • Medullary carcinoma of the Thyroid • Around 30% of MCT patients have germline RET mutations (chr10) • Phaeochromocytoma MEN-2b • Like MEN 2a but without parathyroid involvement and with mucosal neuromas (bumps on lips, tongue, cheeks and eyelids) and marfanoid appearance Pneumonic: Thyroid (Medullary Thyroid Carcinoma) Adrenal (Pheochromocytoma) Primary Hyperparathyroidism5
  • 224. 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
  • 225. 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
  • 226.
  • 227. 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
  • 228. 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 • Lymphadenopathy • Leukaemic meningitis • Testicular Infiltration • Skin Nodules Patient with Acute Promyeloblastic Leukaemia (APML) can present with excessive bleeding owing to primary fibrinolysis and Disseminated Intravascular Coagulation (DIC). Rx includes ATRA! (all-tran retinoic acid)
  • 229. 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
  • 230. Acute Myeloid Leukaemia • Treatment depends on the pts age and the performance score • Chemotherapy – 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 Patient with Acute Promyeloblastic Leukaemia (APML) can present with excessive bleeding owing to primary fibrinolysis and Disseminated Intravascular Coagulation (DIC). This is a separate entity having FAB-M3 morphology and t(15;17) creating the PML-RAR fusion gene, Rx includes ATRA! (all-tran retinoic acid) This needs additional chemo to is essential to eliminate the leukaemic clone.
  • 231. 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
  • 232. 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
  • 233. 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
  • 234. 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
  • 235. 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
  • 236. 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
  • 237. 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
  • 238. 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
  • 239. 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
  • 240. 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
  • 241.
  • 242. 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