Oncology Teaching Clinic - 1 Flashcards
Causes of reducing cancer incidence and mortality
Interdisciplinary efforts, involving many sectors,
organizations, governments and individuals
Prevention, screening, diagnosis and treatment
Research: understanding biology of cancer, etiology,
progression leads to discoveries and means to tackle the disease
Government: policy setting, funding research and
services, equal access to state-of-the-art care, including preventive services
Individuals: awareness, avoiding carcinogens (e.g. smoking), life-style changes
Most significant factors in cancer prevention
Decrease tobacco use (most important)
Dietary measures (i.e. reduce dietary fat and double fiber intake)
Improve physical inactivity, dietary factors, obesity and
overweight
Early screening and detection programs
Wider application of state-of-the-art treatments
Control environmental pollution, infection, radiation and occupational carcinogens
Etiologies of cancer
External causes
- Occupational exposure
- Lifestyle factors
- Biological agents
- Iatrogenic factors
- Known carcinogens: radiation, tobacco, alcohol,
asbestos, aflatoxins, viruses, eg. HPV, hepatitis B and C
Internal causes
- Genetic factors
- Hormonal factors
Smoking related cancers
Major cause: lung, larynx, oral cavity, esophagus
Contributing factor: pancreas, bladder, kidney,
stomach, uterine cervix
Diets a/w cancer risks
Dietary carcinogens: N-nitroso compounds,
heterocyclic aromatic amines, aflatoxin.
High fat, high calorie diet
Low Fiber
Low Micronutrients: vitamins, minerals, nonnutrients.
Low Dietary anticarcinogens: green leafy vegetables,
carotene. Suppress promotion, antioxidants.
Overweight or obese: increased risk of developing cancers of breast, colon, endometrium, esophagus, kidney.
Infections a/w cancer
Human papilloma virus: cancers of the uterine cervix, oropharynx, genital and anal cancers
Hepatitis B virus associated with hepatocellular carcinoma
EBV: NPC
CMV: LPDs
Examples of secondary prevention of cancer
Breast: mammogram/MRI
Colon and rectal cancer and polyps: faecal occult
blood, sigmoidoscopy or colonoscopy
Endometrial and Cervical cancer: Gynaecological
examination and Pap test
Lung cancer: Annual low-dose CT thorax for current
/former smokers (30 pack-year, quit <15 yrs)
Prostate cancer: PSA
Liver cancer: AFP and USG for HB carrier
Criteria for cancer screening
Wilson and Junger criteria
Conditions of cancers suitable for screening:
➢ The disease should be a significant health risk to the population
➢ An at risk population can be easily identified
➢ There is a effective screening test that have low false positive and low false
negative rate
➢ Screening test should be well tolerated and acceptable to the target
population
➢ There is a latency period that allows early detection: pre-malignant
conditions
➢ There is effective intervention/treatment for early disease
Determinants of usefulness of a screening test
Potential harm from the screening test, e.g. radiation
Accuracy of the test: sensitivity, specificity, false positive and false negative rate. Positive predictive value.
Likelihood of the cancer being present
Possible harm for follow-up procedures
Whether suitable treatment for early disease is available and appropriate
Whether early detection improves outcomes:
overdiagnosis, lead time bias
Cost of screening
The extent to which the cancer is treatable
Clinical trials
Ethical justifications
Ethical justifications:
➢ The research design must offer a high probability of generating useful knowledge, ensure scientific validity and reproducibility of results
➢ The probable benefits must outweigh the risks
➢ The selection of subjects must be just, must have Safety monitoring during trial
➢ Subjects must give their informed consent - respect four fundamental ethical principles
➢ Subjects’ rights to privacy and confidentiality must be protected - Declaration of Helsinki for standard of conduct
Phases of cancer drug trial
Phase 1
- Goals: Determine toxicities, bioavailability and pharmacokinetics information, to establish appropriate dosage
- Number of people taking part: 15–30
Phase 2
- Goals: Determining therapeutic efficacy and further defining toxicities and dosage
- Number of people taking part: Less than 100
Phase 3
- Goals: Determine the effects of a treatment relative to the natural history of the disease, and whether a new treatment is more effective than standard therapy or at least as effective but associated with less morbidity
- Number of people taking part: From 100 to several thousand
Phase 4: post-marketing systematic monitoring and recording of outcome data
Randomized Controlled Clinical Trials (RCT)
Unqiue features
Study Design
Design:one group receives investigational therapy and the other group receives either standard therapy, no therapy or a placebo
Features:
- May be “double-blinded”, ie, neither investigator or subject knows who is in treatment or the control group
- Randomization: maximize statistical power, minimize
selection bias, minimize allocation bias (confounding)
- Clinical equipoise (principle of equipoise) provide the
ethical basis for randomization.
Disadvantages of RCT
Limitation of external validity
Costly and takes long time and effort.
Conflict of interest dangers, publication bias
Ethically not acceptable to test in RCT for an obviously effective treatment or the control subject have very poor outcomes
Personal equipoise may not be the same as collective equipoise and clinical equipoise may change with time during the trial
Problems of using placebo and blinding
Does informed consent exempt physicians from Hippocrates Oath of “doing no harm”?
Depersonalization of patients
Critical appraisals in clinical studies
- Metrics to rank clinical trials
Trials ranked on strength of the study design and strength of the endpoints
Ranking allows judgement on the strength of evidence linked to the reported results of a therapeutic strategy.
Study design: randomized, double-blinded controlled clinical trial, retrospective review, case series.
Endpoints: Mortality (survival from the initiation of
therapy), cause-specific mortality, quality of life, or
indirect surrogates of the four outcomes, such as event free survival, disease-free survival, progression-free survival, tumor response rate.
Rank study desings in clinical trials from best to worst
Best:
- Randomized, controlled, clinical trials (double-blinded, nonblinded treatment delivery) – Gold standard
- Meta-analyses of randomized studies offer a quantitative synthesis of previously conducted studies
Moderate:
- Non-randomized, controlled, clinical trials
Worse and worst (descending): Case series
- Population-based, consecutive series
- Consecutive cases (not population-based)
- Nonconsecutive cases
Rand study endpoints in clinical trials from best to worst
Descending order:
1. Total mortality (overall survival): most easily defined and least subject to investigator bias
2. Cause-specific mortality: might miss S/E of therapy
3. Qualty of life: important to patients.
4. Indirect surrogates: subject to investigator interpretation, may not translate into survival/ QoL
* Event-free survival
* Disease-free survival
* Progression-free survival
* Tumor response rate
Outline the ranking for quality of evidence
Level I: evidence obtained from at least one properly
designed randomized controlled trial
Level II-1: Evidence from well-designed controlled
trials without randomization
Level II-2: Evidence from well-designed cohort or
case-controlled analytic studies, preferably from
more than 1 center or research group
Level II-3: Evidence obtained from multiple time
series design with or without the intervention.
Dramatic results in uncontrolled trials
Level III: opinions of respected authorities
Outline the levels of guideline recommendations
Level A: Good scientific evidence suggests that the benefits outweigh risks. Clinicians should discuss with eligible patients
Level B: At least fair scientific evidence suggests that benefits outweigh risks. Clinicians should discuss with eligible patients
Level C: At least fair scientific evidence suggests that there are benefit but the balance between benefits and risks are too close for making general recommendations. Clinicians need not offer it unless there are individual considerations
Level D: At least fair scientific evidence suggests that the risks outweighs benefits. Clinicians should not routinely offer the service to asymptomatic patients.
Level I: Scientific evidence is lacking, of poor quality, or conflicting, the risk versus benefit balance cannot be assessed. Clinicians should help patients understand the uncertainty
Limitations and criticisms of evidence-based medicine
Expensive, time consuming
A lag between when RCT is conducted and when its results are published
A lag between when results are published and when these are properly applied
Publication bias
Generalization from RCT to general practice
Reduces the autonomy of the doctor/patient relationship
Under-researched populations and underresearched questions
Define the Hanahan and Weinberg cariocinogenesis theory
Hanahan and Weinberg: tissue organizational field theory. The hallmarks of cancer include:
- sustained angiogenesis,
- limitless replicative potential,
- evading apoptosis,
- self-sufficiency in growth signals,
- insensitivity to anti-growth signals,
- leading to ability to invade and metastasize
Targeted therapy
- Most useful targeted pathways
Most successful targeted therapies are chemical entities that target or preferentially target a protein or enzyme that carries a mutation or other genetic alteration that is specific to cancer cells and not found in normal host tissue
Clinically most useful targeted biological pathway: epidermal growth and angiogenesis
Examples and MoA of targeted therapies
Imatinib: tyrosine kinase inhibitor to stop proliferation signals
- targets mutant tyrosine kinase of BCR-ABL for Chronic myeloid leukaemia
- target mutant tyrosine kinase of c-KIT +ve GIST
- Other tyrosine kinase inhibitors: Gefitinib, Erlotinib
Anti-EGFR monoclonal antibodies e.g. Cetuximab, Trastuzumab: inhibit epidermal growth factor receptor (EGFR) signaling to downstream proliferation, angiogenesis, metastasis, invasion…etc
Antibody-dependent cellular cytotoxicity mAb: e.g. Rituximab (anti-CD20 mAb)
Examples of cancer biomarkers
Function: diagnosis, predicting prognosis and response to treatment, disease monitoring
Examples:
➢ Diagnostic and prognostic markers, e.g. EBV DNA in
NPC, p16 and HPV in oropharyngeal cancer.
➢ Predictive markers, e.g. Ras mutation in colorectal
cancer, EGFR mutation in lung cancers
➢ Prognostic and predictive markers, e.g. ER, PR, HER2 in CA breast
➢ Disease monitoring: bcr-abl for detecting minimal
residual disease in CML
Causes of targeted therapy failure
Driving vs passenger mutation
Tumor heterogeneity
Continuous evolution in tumor mutation, activation
of alternate pathway
Immunecheckpoint inhibitors
- Function/ MoA
- Examples
Function:
* Immune checkpoints, function at different phases in the immune response to regulate the duration and level of the T-cell response, to limit autoimmunity
* One way tumor cells may evade the body’s immune response is by exploiting the immune checkpoint pathway
* Immune checkpoints offer a molecular target for modulating the immune response and a promising therapeutic target
e.g.
- CTLA-4 inhibitor - Ipilimumab: Affect The Priming Phase of T Cell Activation
- PD-L1 inhibitor - Pembrolizumab : inhibitor downregulation of tumor-specific T-cell activity by binding to PD-1 in the tumor microenvironment
- BRAF inhibitor - Vemurafenib: arrest tumor growth via ERK pathway
