Back to Basics Oncology April 11, 2012 Xinni Song MD FRCPC University of Ottawa Outline Clinical epidemiology of Cancer - How Big is the Problem? Neoplasia –What is it? Risk Factors and Screening Diagnosis and Staging Treatments Quiz Cancer Epidemiology Canadian Cancer Stats More men than women are diagnosed with cancer 51.7% vs 48.3% Over ¼ (27%) of all cancer death due to lung cancer Between 1995-2005, overall cancer mortality has declined Increasing incidence of cancer is mainly due to aging population Proportion of deaths due to cancer and other causes, Canada, 2007 Other, 23.1% Cancer, 29.6% Kidney disease, 1.6% Suicide, 1.5% Alzheimer's disease, 2.5% Influenza and pneumonia, 2.3% Diabetes, 3.1% Diseases of the heart, 21.5% Accidents, 4.2% Chronic lower respiratory diseases, 4.5% Cerebrovascular diseases, 5.9% Adapted from: Ten leading causes of death, Canada, 2007, Statistics Canada Quiz Which cancer has the highest incidence? In men? Prostate Cancer In women? Breast cancer Which cancer has the highest mortality rate? In men? Lung cancer In women? Lung cancer 10 most common cancers in men (percentage of all new cancers in men), Canada, 2011 Lung 14% Colorectal 13% Bladder 6% Non-Hodgkin lymphoma 5% Kidney 3% Prostate 27% Leukemia 3% Melanoma 3% All other cancers 21% Oral 3% Pancreas 2% Data source: Canadian Cancer Statistics 2011 10 most common causes of cancer death in men (percentage of all cancer deaths in men), Canada, 2011 Colorectal 13% Lung 28% Bladder 3% Non-Hodgkin lymphoma 4% Kidney 3% Leukemia 4% Pancreas 5% Prostate 10% Stomach 3% All other cancers 23% Data source: Canadian Cancer Statistics 2011 Esophagus 4% 10 most common cancers in women (percentage of all new cancers in women), Canada, 2011 Lung 14% Colorectal 11% Body of Uterus 6% Thyroid 5% Non-Hodgkin lymphoma 4% Breast 28% Ovary 3% Melanoma 3% All other cancers 20% Pancreas 3% Leukemia 3% Data source: Canadian Cancer Statistics 2011 10 most common causes of cancer death in women (percentage of all cancer deaths in women), Canada, 2011 Lung 27% Colorectal 12% Non-Hodgkin lymphoma 4% Ovary 5% Pancreas 6% Breast 15% Leukemia 3% All other cancers 22% Body of Uterus 2% Brain 2% Stomach 2% Data source: Canadian Cancer Statistics 2011 Cells and Molecules Neoplasm: Characterized by growth and division of cells outside the control of normal regulatory mechanisms Cells have undergone permanent DNA damage Characterized as benign or malignant by their capacity for invasion and metastasis Malignant tumours are divided most broadly into carcinomas and sarcomas, and blastomas in children Exceptions to the rule: Hepatoma, Melanoma, Leukemia,lymphoma, Glioblastoma This figure was adapted from Cell, Vol 100, Hanahan and Weinberg, The Hallmarks of Cancer, pp 57-70, Copyright Elsevier (2000). Genetic Changes Cancers arise due to changes in a cell’s genetic machinery Oncogenes Tumour suppressor genes Oncogenes eg. bcr-abl in CML Genes have dominant transforming properties: one abnormal copy is sufficient Mutation or overexpression leads to unregulated cell division Tumour Suppressor Genes eg. BRCA1/2, RB Genes which are normally involved in the negative regulation of cell cycling Genes have recessive transforming properties: both copies must be abnormal loss of these genes function allows cells to proliferate unregulated, or with reduced restraints CRC Adenoma-Carcinoma Sequence: Vogelstein’s model Mutations can be inherited, or occur through exposures to carcinogens Carcinomas Carcinomas Arise from epithelium Commonest are adenocarcinoma and squamous carcinoma Many others, including germ cell tumours, transitional cell carcinomas, large cell carcinoma, neuroendocrine carcinoma Adenocarcinoma Breast Lung Prostate Most GI, including colon Endocrine malignancies Carcinomas Squamous carcinoma Head and neck cancers Lung Skin Cervix Esophagus anus Germ Cell Tumours Most commonly testicular cancers Ovarian Primary mediastinal Histologic subtypes include teratomas, embryonal carcinomas, yolk sac tumours Sarcomas Much rarer than carcinomas Arise from mesenchymal tissue About 800 soft-tissue sarcomas per year in Canada, and fewer bone sarcomas Named for the tissue they arise from, when known Known tissues of origin Liposarcoma Rhabdomyosarcoma Leiomyosarcoma Osteosarcoma Chondrosarcoma Fat Striated muscle Smooth muscle Bone Cartilage Unknown tissue of origin Malignant fibrous histiocytoma, Ewing’s Sarcoma, alveolar soft parts tumour Summary Histologic characteristics of cancer Excessive cellularity Disrupted architecture Frequent mitoses Unusual cell appearance Large, hyperchromatic nuclei Varying degrees of differentiation Invasion into surrounding tissue Cancer management Screening Diagnosis Staging Treatment Screening Screening is the routine testing of asymptomatic individuals for the presence of cancer Good screening strategy: Test is acceptable to the target population Risk is minimal and cost is reasonable Test is accurate: high sensitivity and specificity Test detects the disease in an asymptomatic (pre-clinical) phase Evidence exists that treatment in the asymptomatic phase improves outcomes Screening test Sn-n-out/Sp-p-in Screening Commonly screened cancers in adults are: Breast (mammography) Cervix (Pap smears) Colon (FOBT/colonoscopy/sigmoidoscopy) Prostate (PSA) Evidence behind screening is surprisingly controversial, in part because of the difficulty of designing studies to avoid bias Screening Lead-time Bias Cancer becomes incurable Symptoms Cancer starts Diagnosis and treatment Time Treatment Diagnosis by screening Death Why Not Screen for All Cancers? Cancer-related factors Cancer Starts Symptoms Incurable Death Preclinical interval too short Incurable Cancer Starts Symptoms Cancer incurable, even if screen detected Death Why Not Screen for All Cancers? Test-related factors Test not sensitive/specific enough Test can’t be applied to whole population Too expensive Insufficient infrastructure/personnel Unacceptable to majority of population Tumour not common enough Risk factors Causal inference: •Temporality- exposure to precede disease •Strength of association – stronger association between an exposure and cancer risk is more likely to be causal than a weaker association •Consistency - association between exposure and outcome demonstrated from other studies •Gradient of effect – increasing levels of exposure are accompanied by increasing in risk •Biological plausibility – if the causal model agrees with present knowledge about biology of the target cells and tissues and the biological effects of the exposure •Specificity – if an association is present between a single exposure and a single disease Risk Factors for cancer Factor Type Attributable Risk Environmental 5% Lifestyle 45% Occupational 4% Pharmacologic 2% Biologic 4% Risk Factors for lung cancer 90% of all lung cancers are attributable to smoking Including 2nd hand smoking 10% occur in non-smokers (younger, female, Asian) Risk increases with # packs smoked, age at onset Tobacco smoke has > 40 identified different carcinogens Women are more susceptible to carcinogenic effects Other risks include some occupational exposures Asbestos, radon, sillica, chromium, arsenic Risk factors for breast cancer Hormonal and Age and gender – older and female reproductive risk Race/ethnicity – Early menarche whites>blacks>hispanic/indians/asi ans Diet/Lifestyle First birth at older age Absence of breast feeding Nulliparity Late menopause HRT Post-menopausal obesity Alcohol Medical history Ionizing radiation Increased breast density Benign breast lesions Environmental Risk factors for breast cancer Family history and genetic risks Breast cancer susceptibility gene 5-6% of all BC BRCA1/2, p53, ATM, PTEN BRCA mutations BRCA1 75 % lifetime risk of breast cancer 50 % lifetime risk of ovarian cancer BRCA2 75 % lifetime risk of breast cancer 25 % lifetime risk of ovarian cancer Melanoma, laryngeal, colon, prostate, pancreas, lymphoma, leukemia Colorectal Cancer : Risk Factors Dietary – most important! High fat, low fibre, high EtOH, low selenium, low calcium Underlying Conditions IBD, prior CRC or polyps, post-radiation Hereditary – 5% FAP (familial adenomatous polyposis) – 1/200, APC gene Gardener’s-intestinal polyps and osteomas Turcot’s – familial polyposis and brain tumors HNPCC (hereditary non-polyposis colorectal ca) 2-4% Genetics: “microsatellite instability = MSI”, MSH2, MLH1,.. Peutz-Jeghers- polyps and pigmented lesions on oral mucosa/lip Family Hx – 10% have Risk factor for colon cancer Family History General population 6% lifetime risk One 1st degree relative: 12% Two 1st degree relatives: 18% 1st degree relative <45 yrs old: 30-42% Diagnosis Early detection of cancer is the key Recommend screening test if available Systematically think about symptoms of cancer Local symptoms of tumour Symptoms from regional (nodal) spread Symptoms from metastatic spread Symptoms from paraneoplastic phenomena Diagnosis Local Symptoms Lung Cough, hemoptysis, SOB, chest wall pain Prostate Urinary obstruction, hematuria Breast Breast mass, skin changes, bleeding from nipple Colon Blood in stool, iron deficient anemia, change in bowel habits Hematological Symptoms of marrow replacement, cytopenias Diagnosis Symptoms from regional Symptoms from Metastatic (nodal) spread Spread Lung (mediastinal nodes) SVCO, esophageal obstruction, hoarse voice, etc Liver Jaundice, abnormal LFT, pain Breast (axillary nodes) Lump under arm Brain Focal neurologic symptoms, seizures Lung Cough, SOB, hemoptysis Bone Pain, pathologic fracture, elevated Alk Phos Diagnosis Paraneoplastic Syndromes Common, non-specific Poor appetite, weight loss, DVT Hormonal syndromes SIADH, Cushing’s, hypercalcemia, carcinoid Neurologic syndromes Lambert-Eaton Syndrome, demyelination syndromes Diagnosis and Staging Definitive diagnosis – tissue needed Purposes of staging Group similar patients together Determine intent of treatment Prognostic purposes Most cancers are staged with a TNM staging system, which leads to overall stage I-IV Tumour Nodal Metastases Treatment Intent of Treatment Radical vs. Palliative Primary Adjuvant Neoadjuvant Modalities of Treatment Surgery Radiotherapy Systemic therapy Treatment: Surgery Indications for Surgery Obtain tissue for diagnosis/staging Definitive treatment of primary tumour Palliation of obstructive/mass effect symptoms Cancer prophylaxis in high-risk cases Esophageal dysplasia/BRCA/FAP/ulcerative colitis Support other procedures Central venous access Rehabilitation/reconstruction Treatment: Radiation Ionizing radiation delivered to tumour and surrounding tissue External Beam Brachytherapy Systemically administered agents Radiation treatment intent Curative as primary treatment Adjuvant for local regional disease control Palliative symptom management External Beam Radiotherapy Treatment: Systemic Therapy Chemotherapy Hormonal Therapy Immunotherapy Targeted therapy :Small molecules/monoclonal antibodies Treatment: Chemotherapy Mechanisms of action Bind to DNA Alkylating agents, platinum agents Antimetabolites 5-FU, methotrexate Bind to microtubules Vinka alkylaoids, taxanes Interfere with topoisomerase Anthracyclines Treatment: Chemotherapy Acute toxicities Mucositis/diarrhea Nausea Hair loss Hypersensitivity reactions Pain Thromoboembolic events Myelosuppression Risk of febrile neutropenia Fatigue Chronic Toxicities Infertility Particularly alkylating agents Leukemogenesis Anthracyclines, alkylating agents Neurotoxicity Cisplatin, taxanes, vinca alkyloids Nephrotoxicity Cisplatin Cardiotoxicity anthracyclines Treatment: Hormonal Therapy Hormone sensitive cancers Breast Prostate Endometrial Ovarian Tumours retain some characteristics of the original tissue Treatment: Monoclonal Antibodies Antibody Trastuzumab (Herceptin) Rituximab (Rituxan) Cetuximab (Erbitux) Bevacizumab (Avastin) Tositumomab (Bexxar) Ibritumomab (Zevalin) Target Tumour HER-2 CD-20 EGFR VEGF CD-20 + I131 CD20 + Y Breast Lymphoma Colon Colon, Lung Lymphoma Lymphoma Treatment: Small Molecules Molecules developed to inhibit specific proteins/enzymes responsible for malignant behavior Imatinib (Glieevec) Gefitinib (Iressa) Erlotinib (Tarceva) Lapatinib (Tykerb) CML, GIST Lung cancer Lung cancer Breast cancer Treatment – Other Palliative care Pain and symptom management End of life care Cancer Survivorship A rapidly expanding field, arising from the recognition that people who have completed curative cancer therapy have ongoing complex medical, social, psychologic issues Lung Cancer - pathology Lung Cancer: NSCLC Stage I-II disease Limited to lung and ipsilateral hilar nodes Surgery gives ~50% long-term survival rate Improved to ~60-65% with adjuvant chemotherapy Stage III Disease Lung and ipsilateral or contralateral mediastinal lymph nodes Seldom amenable to surgery Radiation alone can cure 7-12% Adding chemotherapy increases rate to ~18-25% Stage IV - Metastatic disease Incurable, with median untreated survivals of 4 months With chemotherapy, median survival increases to 10 months 50% of patients have improved symptoms or QoL on chemo Lung Cancer: Small Cell Staged as either Limited or Extensive Limited Confined to one hemithorax Treated with chemo and radiation, with a long-term survival rate of ~25% Median survival untreated: 4 months treated: 12 months Extensive Beyond one hemithorax Treated palliatively with chemotherapy Median untreated survival 6 weeks Median treated survival 9 months Breast Cancer - pathology Invasive ductal carcinoma - 76% Invasive lobular carcinoma – 8% Ductal/lobular – 7% Mucinous(colloid) – 2.4% Tubular carcinoma -1.5% Medullar carcinoma – 1.2% Papillary carcinoma -1.0% Other (micropapillar and metaplastic) – <5% Breast Cancer Staging and Prognostic Markers TNM staging T - tumor extent N- nodal status M- metatstatic disease ER/PR receptor status Histological grade, lymphvascular invasion Her2 status (epidermal growth factor receptor) Gene profiling Breast Cancer Molecular Classification ER(-) ER(+) Solie et al. PNAS 2001; 98:10869-10874 Breast cancer treatment Stage I-II Primary therapy – surgery for the breast lesion + regional LN Systemic therapy – chemotherapy/hormone/targeted therapy Radiation therapy to breast/chestwall/LN Stage III Neoadjuvant systemic therapy Surgery Radiation therapy Stage IV – metastatic Systemic therapy Surgery/radiation as symptom management tools Adjuvant Endocrine Therapy Inhibition of Estrogen-dependent Growth Tamoxifen Estrogen biosynthesis Nucleus Estrogen biosynthesis Aromatase Inhibitors Estrogen Estrogen Receptor Bhatnagar AS, et al. J Steroid Biochem Mol Biol. 2001;77:199-202. Inhibition of growth Tumour cell EBCTCG overview – tamoxifen vs. not Benefits of Chemotherapy Polychemotherapy significantly reduces the risk of recurrence and death Absolute benefit is bigger in patients Under age 50 With ER- tumors With Node(+) disease Polychemotherapy regimens longer than 6 months do not appear to improve survival 1Early Breast Cancer Trialists’ Collaborative Group. The Lancet 352:930-942 Metastatic disease bone > lung > liver > brain Most commonly detected in first 5 years after definitive treatment Treatments try to improve survival and quality of life Median overall survival from time of diagnosis: 18-24 months 5y survival: 5-10% 10y survival: 2-5% Age, disease free interval, # and location of mets, ER status, her2 status Factors Determining choice of Treatment in Advanced Breast Cancer Choice of Treatment Tumour Characteristics Receptors Sites of disease Disease Burden Patient Characteristics Performance Status Age Previous therapy Patient preference Treatment options Toxicity Colon Cancer Stage I-III Typically treated by surgery, with long-term control rates of 40- 85%, depending on stage Adjuvant chemotherapy decreases relative risk of recurrence by 30%, usually offered to pt with stage III or high risk stage II Adjuvant chemo and radiation often used together in rectal, rather than colon cancers Stage IV Palliated by chemotherapy, radiation as indicated Untreated survival ~4-6 months Optimally treated survival ~24 months Prostate Cancer Early stages maybe treated with surgery or radiation More advanced disease is treated with some combination of radiation and hormone therapy (androgen deprivation) Chemotherapy has a limited role, usually just for metastatic disease after hormones fail Q: A unilateral vocal cord paralysis is common in the setting of a mediastinal mass and lung cancer, which vocal cord is more commonly involved? Left vocal cord is more commonly - compression of the left recurrent laryngeal nerve Q: What are the five most common tumors to metastasize to skin ? breast, lung, ovary, colon, kidney Q: What is the most common location of metastasis for renal cell carcinoma? Lung Q: Neutropenic fever is found in 30-40% of patients what is the most common etiology? Gram positive bacteria Q: What syndrome causes diarrhea, flushing, bronchospasm and right sided heart failure? Carcinoid syndrome Q: EKG findings in cardiac tamponade sinus tachycardia, electric alternans, low QRS voltage Q: What is the term used for tumor at the apex of the lung or superior sulcus which may involve brachial plexus, sympathetic ganglion, vertebral bodies, leading to pain, upper extremity weakness and horner’s syndrome? Pancoast tumor Q:What is the most common paraneoplastic syndrome associated with renal cell carcinoma? hypercalcemia (20%) Q: What is the most common pulmonary malignancy associated with hypercalcemia squamous cell carcinoma of the lung Q: Multiple endocrine neoplasia MENI - pancreatic tumors, pituitary adenoma, parathyroid hyperplasia MEN II – parathyroid hyperplasia, medullary thyroid carcinoma, pheochromocytoma, multiple mucosal neuromata Q: Which malignancy is seen at increased frequency in people working in the ruber industry? Bladder cancer - related to exposure to aromatic amines Q: What cancer is asscociated with Barrett’s esophagus? Adenocarcinoma of the esophagus Q: what is the most common solid malignancy in males aged 15-35? Testicular cancer Q: Tumor markers Breast cancer CA15-3, CA27-29m and CEA Ovarian cancer CEA, CA-125 Testicular cancer b-HCG, AFP Hepatocellular carcinoma AFP Q: What is Li-Fraumeni Syndrome? High familial incidence of tumors of soft tissue, breast, brain, bone, leuemia, and adrenal cortex Q: What chromosomal abnormality is associated with young men with malignant mediastinal germ cell tumors Kleinfelter’s syndrome Q: Paraneoplastic syndrome commonly assoicated with small cell lung cancer SIADH Hypercalcemia Ectopic ACTH Eaton-Lambert Syndrome