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
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
