Case 17: cancer Flashcards
1
Q
Tumour grades
A
- Graded by degree of differentiation and growth rate with a scale 1-3.
- Grade 1: well differentiated, slow growing, resemble origin tissue. Better prognosis
- Grade 3: more aggressive, high mitotic rates, poorly differentiated. Worse prognosis
- Anaplastic: poorly differentiated, have few tissue specific features and don’t stain well
- Subjective assessment. Cancers have areas of different grades. Based on the highest grade present.
2
Q
Cytology
A
- Fine needle aspiration (FNA) of cell on a palpable mass: examine cells
- Fluid cytology: ascites, pleural fluid or CSF
- False negatives from sampling errors (especially Sputum), False positives from active infection or abscess formation
- Can examine cells from sputum, urine, cervix, pleural effusions and ascites
- If not sufficient for diagnosis will need biopsy
3
Q
Cytological features of cancer
A
- Increased rate of mitosis
- Altered polarity
- Tumour cell enlargement
- Increased nuclear to cytoplasmic ration
- Pleomorphism (variation in size and shape) of tumour cells and their nuclei
- Clumping of nuclear chromatin
- Distribution of chromatin along the nuclear membrane
- Enlarged nulcei
- Atypical or bizarre mitosis i.e. triporal
- Tumour giant cells with one or more nuclei
4
Q
Cytogenetic analysis
A
- Useful in: leukaemia, lymphoma and some sarcomas
- Shows Chromosomal changes which an be typical in some tumours
- FISH can be used in Ewing sarcoma and peripheral neuroectodermal tumours where there is a translocation between chromosomes 11 and 22. To find specific abnormalities in specific chromosomes
5
Q
Tumour staging
A
- How far the tumour has spread
- Based on: size of the tumour (T), presence of lymph nodes (N) and distant metastases (M)
- Different approaches: FIGO in ovarian cancer, Ann Arbor in lymphoma
6
Q
Cancer: performance status
A
- Assessment of functional capacity, ability to self care and mobility
- Correlates with prognosis and treatment tolerance. Most common scales used are ECOG and Karnofsky score. Range 0-4
- Performance status 3 or 4: don’t tolerate treatment and chemo can shorten lifespan
7
Q
ECOG performance status
A
- 0: fully active, able to carry out normal activities without restriction and analgesia
- 1: restricted in strenuous activity but ambulatory and able to carry out light work or pursue a sedentary occupation. Includes patients fully active with analgesia
- 2: ambulatory and capable of self care but unable to work. Up and about for >50% of waking hours
- 3: capable of limited self care. Confined to a bed or chair for >50% of waking hours
- 4: completely disabled. Unable to carry out any self care and permanently confined to a bed or chair.
8
Q
Cancer MDT
A
- Involves the physician, surgeons, radiologist, pathologist and specialist nurses
- Plan diagnosis and treatment
- May include additional support: physiotherapy, psychological support, symptom control, nutritional care or rehabilitation in the post op period
- Can run combined clinics i.e. triple assessment in breast cancer: improves communication between team members and reduces delays for the patient
- Discuss palliative cases
- Auditing and recruitment into clinical trials
9
Q
Systemic treatment intent
A
- Metastatic disease: indication for the majority of chemotherapy, for palliative use
- Adjuvant therapy: given after surgery to clear remaining microscopic cancer
- Primary therapy (neoadjuvant): given before cancer to reduce bulk
- Chemoprevention: prevent malignant transformation in high risk patient i.e. Tamoxifen in breast cancer
- When treating cancer you need to state whether the intent is curative or palliative
10
Q
Palliative chemotherapy
A
- For the majority of patients with widespread metastasis
- Aim is to improve symptoms and QOL
- Treatment should be well tolerated with few side effects
- Can have limited toxicity but shouldn’t effect performance status
- Can be used when patient has exhausted other treatment
- Main indication for chemotherapy
11
Q
Adjuvant chemotherapy
A
- Used after another another intervention i.e. surgery
- Aim is disease free and improve survival. Try to eradicate any remaining micro metastatic disease which remains
- Will accept greater toxicity
- Treatment has increased morbidity and mortality
- Chemo that has previously shown high response in palliative setting
- You measure response by assessing time to progression
12
Q
Neoadjuvant chemotherapy
A
- Chemotherapy is administered first before another procedure (surgery)
- Can result in a reduced requirement for surgery, increase the likelihood of successful debulking, reduce the duration of hospitalisation and improve patients health prior to surgery
- Help reduce the volume of disease to help make the second intervention possible. Cn reduce patients need for analgesia and mean they are discharged quicker.
- Most commonly used for an inoperable patient (technical or fitness factors), the volume of disease is too large or they don’t have the fitness for the anaesthetic
- Measure response by assessing size of tumour through imaging
- Can be used to determine adjuvant goals
13
Q
Chemoprevention
A
- Treatment used in at risk groups to prevent the development of cancer, helps improve survival
- Agents used are to modify risk and improve survival
- Only accept very low incidence of toxicity
- Many chemotherapy agents are themselves carcinogenic or can cause adverse side effects.
- Impact on overall survival needs careful evaluation
14
Q
Chemotherapy treatment approaches
A
- Chemo should start within 31 days of agreeing treatment with clinician and 62 days from the initial referral if 2ww
- Commonly: chemo is administered every 21-28 days which is one cycle
- A course of treatment is usually 6 cycles
- Results of different cycles are evaluated in clinical trials
15
Q
Chemo: low and high dose therapy
A
- Low dose: standard approach, most palliative chemo is given this way. May have cytotoxicity but only for a short time (few days).
- High-dose therapy: increased dose which kills more cells but results in more bone marrow toxicity. May have neutropenia for a few weeks (6-7). High risk of complications i.e. unusual infections. Use G-CSF. Allows more drug to be administered in the same schedule but the total dose can be less than intended due to limitations of non-haematological malignancy
16
Q
Chemo: dose dense therapy and alternating therapy
A
- Dose dense therapy: fractionating the intended dose of drug and administering each fraction more frequently (often weekly).
- Alternating therapy: involves giving different drugs in an alternating manner (1-2 weeks). Commonly used in Haematological malignancies, when cells might respond to different agents. Used to overcome drug resistance.
17
Q
Low dose chemo bone marrow recovery
A
G-CSF helps the bone marrow to recover. IM injection once a day up to 7 days The next cycle of chemo is started once the bone marrow function has recovered (neutrophils >1.0x109/L and platelets >100x109/L)
18
Q
High dose chemo bone marrow recovery
A
use GCSF to recover the bone marrow. Alternatively autologous stem cells are used from the patient from a previous chemo cycle and readministered to the patient as if they were having a blood transfusion. Repopulates the bone marrow quicker (16-21 days)
19
Q
Complications of chemo
A
- Low dose: bacterial infection
- High dose: unusual infections like fungi or protozoal
20
Q
Benefits of dose dense therapy
A
- Each individual dose produces less toxicity but the anticancer effect is related to the accumulative dose over time
- Such an approach can overcome drug resistance, produce a greater cell kill and in some cases produce a response with weekly administration when the 3-weekly schedule doesn’t work.
- May choose due to previous lack of response, low fitness or comorbid conditions
- Used commonly in breast and ovarian cancer
21
Q
Sites of action of cytotoxic drugs
A
- Purine and Pyrimidine synthesis: 6-Merceptopurine
- Ribonucleotides: Methotrexate, 5-Fu
- DNA formation: Cytarabine
- DNA replication; Alkylating agents
- Microtubules (Mitotic spindle formation) which is used in Mitosis and cell division: Vinca alkaloids, Taxanes
22
Q
Sites of action of cytotoxic agents: cell cycle
A
- Alkylating agents: whole cell cycle
- Antimetabolites and Antibiotics: Some of growth phase and synthesis
- Mitosis: Vinca alkaloids, Taxoids
- Cells that are arrested at the G2:M interface are more susceptible to other treatments like radiotherapy. Done with Vinca alkaloids
- Cells that are not growing and are dormant tend not to respond to chemotherapy. Tumours in hostile environments like hypoxia can become dormant and resistant to chemotherapy.
23
Q
Factors which grow or inhibit the cell cycle
A
- Growth: Growth factors (G-CSF, TGF-beta
- Inhibits: p15, p16, p18, p19, p21, p27, p57. p53 activates the other inhibitory factors.
- These break the cell cycle and then accelerate it The breaks help the cell to repair
24
Q
Issues and solutions to chemotherapy
A
- Issues: poor success, response determined by cell types, resistance
- Potential ways to improve treatment: improve existing drugs, New targets, Targeted therapy, Improve identification of new compounds
25
Cancer treatment: improving existing therapy
- Analogue development: Improved tolerability, increased spectrum of activity, oral drugs
- Altered delivery: Change dose, Continuous infusion, Liposomal formulations, High dose chemotherapy
26
Cell cycle abnormalities found in cancer
- p16: deletions, mutations, DNA methylation
- CDK4, CDK6: amplification mutation
- Cyclin D: Amplification
- p27: low expression, poor prognosis
- Cyclin E: Overexpression, poor prognosis
- Cyclin A: overexpression, poor prognosis
- Cell markers can be used for evidence of cancer, evidence of response, prognostic information and might determine how effective therapy is. Take a biopsy before and after treatment and see how expressed these proteins are (benefit of Neoadjuvant approach.
27
Cell markers in different cancers
- Inactive Rb gene: Retinoblastoma, SCLC
- Amplified Cyclin D1: Head and neck, Oesophageal
- Deleted p16: Giloma, Mesothelioma, Pancreas
- Mutated p16: Biliary tract, Pancreas, NSCLC
- Amplifies Cdk4: Sarcoma, Giloma
- Identification of cell markers can indicate which treatment will be effective or not
28
Actin
on the cytoskeleton, forms pseudopodium which is how cells migrate. Neutrophils migrate along the endothelium (wall of blood vessels). So chemo which attacks actin and microtubules can stop neutrophils from working. As they are unable to move and infiltrate sites of inflammation, cant fight cancer.
29
How a primary tumour infiltrates
- Primary tumour is attached to the basement membrane
- The basement membrane is degraded by invadopodia
- Carcinoma cells migrate on ECM fibres into the blood stream
- Migrates in blood vessel as a single cell metastasis
- Treatment can be used to slow the rate of metastasis which is what ultimately kills the patient
30
Tumour growth and invasion
1. Isolated tumour cell
2. Limited proliferation: production of angiogenic factors
3. Production of blood vessels in the tumour: cell migration, angiogenesis, tumour growth, vascular maintenance
4. Protease production
5. Invasion of blood vessels: cell migration and vascular transport
6. Attachment to distant endothelium on adhesion molecules: extravasation/invasion
7. Formation of micro metastatic foci
8. Establishment of metastatic foci
31
Cancers inducing new blood vessel growth
- In order to transport nutrients and oxygen to the tumour
- Cant grow beyond 1mm without blood vessel growth
- Process of angiogenesis
32
Interactions at tumour cells
Endothelial cells, Pericyte, Fibroblast, Lymphatic cell, Neutrophil, Macrophage, Mast cell, Basement membrane and extracellular matrix. Sometimes when tumour cells appear to reduce in size it is actually the human cells around it.
33
The 10 hallmarks of cancer and the treatment which targets them
- Evading growth suppressors: Cyclin dependent kinase inhibitors
- Avoiding immune destruction: Immune mediated anti-CTLA4 mAb
- Enabling replicative immortality: Telomerase inhibitors
- Tumour promoting inflammation: selective anti-inflammatory drugs
- Activating invasion and metastasis: Inhibitors of HGF/c-Met
- Inducing angiogenesis: inhibitors of VEGF signalling
- Genome instability and mutation: PARP inhibitors
- Resisting cell death: Proapoptotic BH3 mimetics: resisting cell death
- Deregulating cellular energetics: Anaerobic glycolysis inhibitors
- Sustaining proliferative signalling: EGFR inhibitors
34
Assessment of toxicity: cancer treatment
- Anticancer treatment is given at the maximum dose tolerated by the patient and adverse effects are inevitable.
- There are common toxicity criteria (CTC) scales that rate the severity of several hundred side-effects on a 0-4 scale.
- Gives objective measurement and comparison over time
35
Evaluation of treatment (cancer)
- The evaluation of treatment: assessment of overall survival duration, response to treatment, remission rate, disease-free survival and response duration, quality of life, and treatment toxicity
- Tend to assess after cycle 3 to exclude disease progression
- Overall survival rate: percentage of people alive after a certain period of time (normally 5 year). Con: takes time
- Remission rate: percentage of patients that achieve a state where the cancer is no longer detectable
- Disease free survival: length of time after treatment where the patient survives with no symptoms or signs of the disease
- Uniform criteria include the response evaluation criteria in solid tumours (RECIST)- means you can compare treatment
36
RECIST criteria
- Complete response (CR): Disappearance of all target lesions
- Partial response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD
- Progressive disease (PD): At least a 20% increase in the sum of the LD of target lesions. Taking as reference the smallest sum LD recorded since the treatment started and at least 5mm increase or the appearance of one or more new lesions
- Stable disease (SD): In-between PR and PD, taking as reference the smallest sum LD since the treatment started
37
Complete and partial remission
- Complete remission where all signs and symptoms of cancer have disappeared, although cancer still may be in the body. Up to 5 years. Also not detectable by bloods or imaging
- In partial remission, some, but not all, signs and symptoms of cancer have disappeared
38
Evaluation of treatment: response
- Assessed by RECIST 1.1 criteria with pre treatment documentation of target and non-target lesions
- All lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs should be noted
- Pick the largest lesions and those easily measured
- A sum of the longest diameter (LD) for all target lesions will be calculated and recorded as the baseline sum LD. All other lesions should be identifies as non-target lesions and recorded at baseline
39
Evaluation of cancer treatment: measurable and non-measurable
- Measurable disease: at least one lesion you can measure its longest diameter (LD). At least >10mm when assessed by CT/MRI and clinical examination, or >20mm with X-ray. For malignant lymph nodes the short axis >15mm. Use the same imaging technique throughout
- Non measurable disease: include more subjective measurement like tumour marker levels, presence of ascites or pleural effusion.
- Residual disease: cancer left after treatment completion, Indicates resistance to treatment and is an adverse prognostic factor. May need extra treatment. If hard to determine investigate the residual lesion with fine needle aspirate/biopsy to confirm.
40
Bladder cancer
- Arises from the urothelial cells on the bladders inner surface
- Majority which present are non invasive and have good prognosis
- Most are urothelial carcinomas (transitional cell carcinoma)
41
Bladder cancer risk factors
- Age, male, FH
- Pelvic radiation for prostate
- Transitional cell carcinoma: smoking, exposure to aniline dyes (printing and textiles), Rubber manufacture, Cyclophosphamide
- Squamous cell carcinoma: Schistosomiasis, smoking
42
Bladder cancer: classification
- Transitional cell carcinoma: >90%
- Squamous cell carcinoma
- Adenocarcinoma
43
Bladder cancer transition cell carcinoma
solitary lesions or multifocal. Majority (70%) have a papillary growth pattern. Are superficial and have a good prognosis. The rests are mixed papillary and solid growth or pure solid growth, these are more prone to invasion and have a worse prognosis.
44
Bladder cancer clinical features
- Haematuria: most common presenting symptom, typically painless (gross or microscopic)
- Dysuria, frequency, urgency and suprapubic pain
- Systemic symptoms: weight loss, fatigue or anaemia
- Obstruction: retention, hydronephrosis
45
2WW for bladder cancer
- aged 45 and over and have: unexplained visible Haematuria without urinary tract infection or visible haematuria that persists or recurs after successful treatment of urinary tract infection, or
- aged 60 and over and have unexplained non‑visible haematuria and either dysuria or a raised white cell count on a blood test.
46
Bladder cancer investigations
- Urinalysis: blood, RBC casts
- FBC (anaemia), U&E
- Urine cytology
- Cystoscopy, Biopsies or TURBT
- Pelvic MRI: local spread
- CT: distant disease
- PET CT: nodes of uncertain significance
47
Staging of bladder cancer
- Staging if non-invasive: IV pyelogram or CT/MR urogram
- Staging if invasive: CT chest abdo pelvis including CT urogram
48
Bladder cancer: staging
- Non-muscle-invasive bladder cancer (not invading the muscle layer of the bladder)
- Muscle-invasive bladder cancer (invading the muscle and beyond)
- TNM: T (tumour), N (lymph node) and M (Metastasis)
49
Non muscle invasive bladder cancer includes
- Tis/carcinoma in situ: cancer cells only affect the urothelium and are flat
- Ta: cancer only affecting the urothelium and projecting into the bladder
- T1: cancer invading the connective tissue layer beyond the urothelium, but not the muscle layer
- Invasive bladder cancer includes T2 – 4 and any lymph node or metastatic spread.
50
Management: Non-Muscle Invasive Bladder Cancer (NMIBC)
- Transurethral resection of bladder tumor (TURBT): provides diagnosis, staging, and initial treatment.
- For high-risk (carcinoma in situ or other high risk): intravesical BCG immunotherapy.
- Post op itravesical chemo
- Maintenance therapy: BCG maintenance therapy may improve outcomes in high-risk patients.
- Second line surgery: cystectomy with creation of urostomy eith ileal conduit
