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Back to Basics Oncology 13 April 2010 Garth Nicholas Outline • • • • • • How Big A Problem? Cells and Molecules Risk Factors and Screening Diagnosis and Staging Treatments Specific Cancers How Big A Problem? • 171000 new cancers in Canada in 2009 • 75300 cancer deaths in 2009 • Projected to be the commonest cause of death in Canadians in 2010. How Big A Problem? • Lifetime risk of developing cancer for Canadians – Women 38% – Men 43% • 31% of PYLL due to cancer (954 000 years) • 65% of diagnoses and 80% of deaths are in people over the age of 60 • ~7500 cases (4.4%) in people younger than 20 Canadian New Cases and Deaths Tumour New Cases Deaths Prostate Lung 25500 23400 4400 20500 Case-Fatality Rate 0.17 0.94 Breast 22900 5400 0.24 Colon 22000 9100 0.41 NHL 7200 3200 0.44 Women Men Women Men Cells and Molecules • Cancer: – Characterized by growth and division of cells outside the control of normal regulatory mechanisms – Characterized as benign or malignant by their capacity for metastasis – Benign tumours designated by the suffix -oma – Malignant tumours are divided most broadly into carcinomas and sarcomas, and blastomas in children • Exceptions to the nomenclature rules: – Hepatoma – Melanoma – Leukemia – Glioblastoma 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 Carcinomas • Adenocarcinoma – Breast – Lung – Prostate – Most GI, including colon – Endocrine malignancies – Characterized by gland formation Carcinomas • Squamous carcinoma – Head and neck cancers – Lung – Skin – Cervix – Esophagus – Anus Carcinomas • 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 parenchymal tissue – About 800 soft-tissue sarcomas per year in Canada, and fewer bone sarcomas – Named for the tissue they arise from, when known Sarcomas – 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 Others • Hematologic malignancies – Do not fit well into the carcinoma/sarcoma spectrum – Technically, lymphomas are considered sarcomas (reticulosarcoma) while leukemias are considered carcinomas – Practically, no one makes this distinction Blastomas Aggressive childhood tumours – Neuroblastoma, retinoblastoma, medulloblastoma – Named for their histologic resemblance to cells at the centre of blastocytes Summary • Histologic characteristics of cancer – Excessive cellularity – Disrupted architecture – Frequent mitoses, sometimes bizarre – Unusual cell appearance • Large, hyperchromatic nuclei – Varying degrees of differentiation – Invasion into surrounding tissue Genetic Changes • Cancers arise due to changes in a cell’s genetic machinery • These changes involve genes that are divided into two major groups – Oncogenes – Tumour suppressor genes Genetic Changes • Oncogenes – Are altered forms of normal genes called proto-oncogenes – Genes have dominant transforming properties: one abnormal copy is sufficient – Proto-oncogenes tend to function in normal cell cycling and differentiation – Mutation or overexpression leads to unregulated cell division Genetic Changes • Tumour Suppressor Genes – Genes which are normally involved in the negative regulation of cell cycling – Genes have recessive transforming properties: both copies must be abnormal – Classic example is retinoblastoma – Loss of these genes allows cells to proliferate unregulated, or with reduced restraints Genetic Changes • CML is driven by the bcr-abl oncogene (Philadelphia chromosome) Genetic Changes Genetic Changes • In reality, single mutations are usually insufficient for malignant transformation, and cancer cells contain a number of genetic abnormalities, many of uncertain significance • Hematologic cancers have fewer genetic abnormalities than solid tumours Risk Factors • Risk factors for cancer are difficult to study – Long interval between exposure and disease – Many exposures to agents of unknown significance – Unclear correlation between carcinogenesis in laboratory and in real world • ?Threshold levels for carcinogenesis – IARC publishes a list of known causes of cancer, and estimates of their significance Risk Factors Factor Type Attributable Risk Environmental 5% Lifestyle 45% Occupational 4% Pharmacologic 2% Biologic 4% Risk Factors • Environmental Causes – Aflatoxin – Erionite – Radon – Solar Radiation Hepatocellular carcinoma Mesothelioma Lung (RR=2) Melanoma (RR=3) Risk Factors • Lifestyle Causes – Tobacco Lung (RR=12) Larynx (12) Oral cavity (5), esophagus(4), kidney (3), bladder (3), pancreas (2) – Smokeless tobacco Oral Cavity (2) – Betel and tobacco Oral Cavity (9) – Alcohol Oral cavity (5), esophagus(4), larynx (3) liver (3) – Diet Risk Factors • Occupational (35 factors listed) – Benzene – Asbestos Leukemia (RR=3) Mesothelioma (6), lung (3) • Pharmacologic (18 factors listed) – Alkylating agents (9) – Immunosuppressants(2) – Hormones (5) – Others (2) Leukemias Lymphomas Endometrium Risk Factors • Biologic Causes – – – – – – – – – EBV Burkitt’s lymphoma (RR=30) H. pylori Gastric (4) HBV Liver (100) HCV Liver (20) HIV KS (1000), NHL (100) HPV t16,18 Cervix (20) HTLV-1 Adult T-cell lymphoma (4) O. viverrini Cholangiocarcinoma (5) S. haematobilium Bladder (5) Screening • Screening is the routine testing of asymptomatic individuals for the presence of cancer • Underlying screening is the assumption that cancers detected at the asymptomatic stage are more amenable to therapy Screening • Cancers commonly screened for in adults are: – Breast (mammography) – Cervix (Pap smears) – Colon (Barium enema/colonoscopy/FOBT) – Prostate (PSA) • Evidence behind screening is surprisingly contentious, in part because of the difficulty of designing studies to avoid bias Screening • Lead-time Bias Cancer becomes incurable Symptoms Cancer starts Diagnosis and treatment Time Treatment Diagnosis by screening Death Screening • Length Time Bias * * * * * * * * * 1 2 3 4 Screening • Breast – Recommendations are for annual breast exam and biannual mammography starting at age 50 (?ending at age 74) • Cervix – Recommend Pap smears annually for first three years after becoming sexually active, then every two years until age 70 – Frequency is different if any test is abnormal Screening • Prostate – Ontario guidelines state that “Healthy men without symptoms may decide to have a PSA test after talking to their family doctor or if they are at high risk for prostate cancer ("first degree" relatives with the disease, men of African ancestry).” – Not covered by OHIP because no trial has ever shown a survival advantage to screening Screening • Colon – Methods include fecal occult blood testing (FOBT), colonoscopy, Ba enema, sigmoidoscopy – Ontario is currently running a pilot program of FOBT in 12 areas to inform eventual development of a provincewide policy – Colonoscopy is widely used despite paucity of evidence 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 Diagnosis • Impossible to list all possible symptoms of cancer • Systematically think about symptoms in four categories: – Local symptoms of tumour – Symptoms from regional (nodal) spread – Symptoms from metastatic spread – Symptoms from paraneoplastic phenomena Diagnosis • Local Symptoms – Lung • cough, hemoptysis, SOB, chest wall pain – Prostate • urinary obstruction, hematuria – Leukemia • Symptoms of marrow replacement, cytopenias – Breast • Breast mass, bleeding from nipple Diagnosis • Symptoms from regional (nodal) spread – Lung (mediastinal nodes) • SVCO, esophageal obstruction, hoarse voice, etc – Breast (axillary nodes) • Lump under arm Diagnosis • Symptoms from Metastatic Spread – Liver • Jaundice, abnormal LFT, pain – Brain • Focal neurologic symptoms, seizures – Lung • Cough, SOB, hemoptysis – Bone • Pain, pathologic fracture, elevated Alk Phos 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 • Ultimately, diagnosis requires tissue – Fine needle aspirate – Core biopsy – Excisional biopsy – Open biopsy Staging • The second part of diagnosis is staging • Purposes of staging – Group similar patients together – Determine intent of treatment – Prognostic purposes • Standard staging tests vary by cancer, but may include bone scans, marrow biopsy, imaging of brain/thorax/abdomen Staging • Most cancers are staged with a TNM staging system, which leads to overall stage I-IV – Tumour – Nodal – Metastases Staging • Breast Cancer T1 T2 T3 T4 1-20 mm 20-50 mm >50 mm Chest wall, skin, or inflammatory N0 N1 N2 N3 No Nodes Mobile axillary nodes Fixed Axillary Nodes Internal Mammery Nodes M0 M1 No distant metastases Distant metastases present Staging T 1 1 2 2 3 3 Any 4 Any Any N 0 1 0 1 0 1 2 Any 3 Any M 0 0 0 0 0 0 0 0 0 1 Stage 1 2A 2A 2B 2B 3A 3A 3B 3B 4 Only people who work with cancer every day actually memorize these. Staging • Another staging system worth remembering is the Ann Arbour stages for Hodgkin’s disease Stage I II III IV Suffix Definition Involvement of a single node region Two or more node regions on same side of diaphragm Lymph node regions on both sides of the diaphragm Involvement of one or more extranodal sites in addition to the site for which the suffix “E” is used (see below) A B E X Absence of “B Symptoms” Presence of “B Symptoms”: fever, drenching night sweats, loss of >10% body weight in preceeding 6 months Involvement of single extranodal site contiguous with nodal disease Bulky disease (nodal mass >10 cm, or mediastinum widened >1/3) Treatment • Intent of Treatment – Radical vs. Palliative – 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: Surgery • Surgery has a central role, as 90% of solid tumours that are cured have surgery as part of the treatment plan • Appropriate primary cancer surgery includes resection of primary tumour and associated lymphatic drainage • Surgical debulking is appropriate in only a tiny minority of cases – Ovarian cancer, Burkitt’s lymphoma Treatment: Surgery • In few cases is it appropriate to resect metastatic disease: – Solitary brain metastases – Anatomically amenable liver metastases from colon cancer – Pulmonary metastases from sarcomas – Residual disease in germ cell tumours Treatment: Radiation • Ionizing radiation delivered to tumour and surrounding tissue – External Beam – Brachytherapy – Systemically administered agents • Not understood exactly how radiation causes cell death – DNA likely target – Differential ability of tumour and normal cells to repair radiation damage Brachytherapy External Beam Radiotherapy Treatment: Radiotherapy • Long-Term Complications – Most related to long-term microvascular changes – Radiation pneumonitis/pulmonary fibrosis – Demyelination/memory changes/dementia – Infertility – Second cancers Treatment: Systemic Therapy • • • • Chemotherapy Hormonal Therapy Immunotherapy Small molecules/monoclonal antibodies Treatment: Chemotherapy • Based on the (now disproved) notion that cancer cells divide more rapidly than normal cells • Chemotherapy drugs tend to interfere with a cell’s ability to divide normally • Cells which cannot divide normally should undergo apoptosis 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 – Myelosuppression • Risk of febrile neutropenia Treatment: Chemotherapy • Chronic Toxicities – Infertility • Particularly alkylating agents – Leukemogenesis • Anthracyclines, alkylating agents – Neurotoxicity • Cisplatin, taxanes, vinca alkyloids – Nephrotoxicity • Cisplatin 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 (Glivec) – Gefitinib (Iressa) – Erlotinib (Tarceva) – Lapatinib CML, GIST Lung cancer Lung cancer Breast cancer Treatment • 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 • Divided into: – Non-small cell – 85% • Adenocarcinoma – Bronchoalveolar carcinoma • Squamous • Large Cell – Small cell – 15% Lung Cancer: NSCLC • Typically staged by CT thorax, abdo, head, bone scan, and mediastinoscopy if surgery is considered • Stage I-II disease – Limited to lung and ipsilateral hilar nodes – Surgery gives ~50% long-term survival rate – Improved to ~60-65% with adjuvant chemotherapy Lung Cancer: NSCLC • Stage III Disease – Lung and ipsilateral or contralateral mediastinal lymph nodes – Seldom amenable to surgery – Radiation alone can cure 7-12% – Adding chemotherapy increases rate to ~1825% – Treatment can be difficult, and many patients are not candidates Lung Cancer: NSCLC • 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 Lung Cancer: SCLC – Extensive • • • • Beyond one hemithorax Treated palliatively with chemotherapy Median untreated survival 6 weeks Median treated survival 9 months Breast Cancer • In many ways, treatment by stage is similar to lung cancer: – Stage I-II • Limited to breast and axillary lymph nodes • Surgery alone cures 40-90% • Adjuvant chemotherapy or hormonal therapy reduces relative risk of relapse by ~30% • Adjuvant radiation reduces risk of local relapse after breast-conserving surgery Breast Cancer • Stage III – Locally advanced disease, often not amenable to surgery initially – Many respond to neoadjuvant chemotherapy, and go on to surgery • Stage IV – Palliative, with hormones, chemotherapy, monoclonal antibodies, radiation as indicated – Median survival ~1.5 years, but lots of variation Colon Cancer • Staged by CT abdo, chest X-ray, bone and brain scan if rectal, rather than colon • Stage I-III – Typically treated by surgery, with long-term control rates of 40-85%, depending on stage – Adjuvant chemotherapy decreases relative risk of recurrence by 30% – Adjuvant chemo and radiation often used together in rectal, rather than colon cancers Colon Cancer • Stage IV – Palliated by chemotherapy, radiation as indicated – Untreated survival ~4-6 months – Optimally treated survival ~24 months Prostate Cancer • Treatment determined in large part by grade of tumour, and age of patient, in addition to stage • There is controversy about treatment at virtually all stages of disease • For cancer limited to the prostate, the controversy is between radical radiation and surgical resection Prostate Cancer • More advanced disease is treated with some combination of radiation and hormone therapy (androgen deprivation) • Chemotherapy has a limited role, usually just for metastatic disease after hormones fail Generic Treatment Algorithm for Solid Tumours • Localized cancer (Often stage I-II) – Surgical resection with adjuvant chemo or hormones as appropriate • Locally Advanced Cancer (Often stage III) – Combined chemo and radiation, with curative intent • Metastatic Cancer (Stage IV) – Palliative chemo, hormones, + radiation