Principles of Cancer Treatment Flashcards
Cancer growth kinetics
- logarithmic
- once detectable, tumour tends to grow quickly
- Gompertzian curve
Gompertzian curve
- 3 phases (lag, log & stationary)
- >30 generations then clinically detectable (10^10)
Tumour growth equilibrium
- slope of the curve depends on 3 factors
1. Ratio of cell division to cell loss
2. Growth fraction
3. Doubling time (TD) - which in turn depends on host factors
eg vasculature, presence of cell populations, space restrictions & necrosis
Doubling time (TD)
- time taken for the tumour to double its mass
- solid have longer TD than hematological malignancies
(2-3 months vs 24h) - large variations in TD
Metastasis
- can begin early before the tumour is clinically detectable
- through 2 pathways
1. Blood
2. Lymphatic system
MOA of metastasis
- Tumour cells release lytic enzymes
eg proteases - Dissolution of the basement membrane by lytic enzymes
- Invasion & movement of the tumour cells through the defect due to increased cell motility & decreased cell-cell adhesion
- Binding of tumour to the basement membrane at another site through the mediation of altered receptors on the cell surface
Metastatic sites
- metastatic patterns depends on the tumour type eg colon cancer to liver cancer (close proximity) - can be anywhere - common : ~ liver ~ lungs ~ lymph nodes ~ brain ~ skin ~ bone
Goals of cancer therapy (4)
- Curative
- Maintenance of quality & duration of life
- Symptom relief (palliative treatment)
- Clinical trials for experimental therapies
- not the main goal, only when all options fail
- goals must be negotiated with patient, family, physicians & healthcare team
Characteristics of an ideal treatment (3)
- must be safe, effective & discriminating
Safe : few side effects
Effective : return the patient to former state of health
Discriminating : limited to cancer cells only
Treatment modalities of cancer (3)
- Surgery
- Radiation
- Chemotherapy
Surgery (4)
- oldest cancer treatment
- curative for localised or primary cancer
- reduce the size of tumour to increase efficacy of radiotherapy, chemotherapy & other therapies
- play a major role in diagnosis, staging, relief of symptoms, reconstruction & prevention
Radiation (4)
- destruction of cancer cells by ionising radiation
- MOA is through generation of free radicals
- may selectively destroy rapidly dividing cancer cells > normal cells
- radiocurability depends on :
1. size
2. location of tumour
3. type of tumour
4. tumour radiosensitivity
Dose limiting factor of radiation therapy
+2 strategies to overcome
Normal tissue damage
- early effects on rapidly dividing normal cells
- late effects on organs
- newer technologies to minimise normal tissue damange
- fractionate radiotherapy
Toxicities of radiation therapy
- fetal death
- GI ulcer & hemorrhage
- hepatitis
- bone marrow effects
Uses of radiotherapy in cancer (4)
- bone marrow transplant (total body irradiation)
- supplement surgery
- palliation of pain
- relief of obstruction/compression
Chemotherapy (3)
- drug therapy for cancer
- most useful for systemic or disseminated disease (including micrometastases)
- adjunct to surgery, radiotherapy & palliation
Principles of chemotherapy (4)
- cell kill
- greatest effect
- therapeutic window
- monotherapy?
- kills a constant proportion of tumour cells
(( repeat treatment cycles )) - greatest effect on actively dividing cells
(( treat asap when disease in early stage )) - narrow therapeutic window
(( know intent to treat & monitor side effects))
Hence, treatment is a balance of efficacy & toxicity - combination chemotherapy may be used to improve treatment outcome
(( where possible ))
Balance between efficacy & toxicity tolerance depends on __
Treatment goal (3)
- curative
- maintenance of quality & duration of life (extend life)
- palliate symptoms
Efficacy & toxicity tolerance (curative) (3)
- high tolerance for side effects
- concerns over delayed & late side effects
- avoid treating those who are already cured (over treatment)
Efficacy & toxicity tolerance (extend life) (3)
- moderate tolerance for side effects
- concern over value of added time
- treat when added time outweighs side effects
Efficacy & toxicity tolerance (palliative care) (3)
- low tolerance for side effects
- symptoms control
- treat only when not treating leads to lower QOL
Advantages of combination chemotherapy (3)
- maximum cell kill within acceptable toxicity
- broad coverage against multiple cell lines (use diff MOA)
- slower emergence of resistant strains
Disadvantages of combination chemotherapy (4)
- multiple toxicities with greater patient discomfort
- impact of dose effect (additive dose effect)
- complicated to administer
- more expensive
Protocols
- guidance on the different “cocktails” of chemotherapy to use
Reasons for protocols (4)
- different tumours responds to different “cocktails” of chemotherapy
- efficacy established during clinical trials
- numerous combinations hence it is impt to know the rationale behind the combinations
- diff institutions have different protocols for treatment
Calculation for dose of chemotherapy is based on __
Body Surface Area (BSA)
BSA formula
square root [(height + weight)/3600]
height in cm
BSA in m^2
Why is BSA used to calculate dose?
- provides a more accurate cross-species comparison of activity & toxicity for many drugs
- more closely related to cardiac output which determines blood flow to liver and kidney, subsequently determines drug elimination
Importance of “drug rest” (2)
- to allow for normal cells to recover
- achieve optimal therapeutic benefit with minimal toxicity
How to intensify dose? (2)
- Reduce dosing interval
2. Increase the dose
Selection of chemotherapy regimen steps (6)
- Determine histological diagnosis, tumour staging & prognostic variables
- Identification of treatment options & determine benefits
- Assessment of comorbid conditions & psychosocial environment
- Determine treatment related risks
- Assessment of risk vs benefits
- Selection of therapeutic regimen
Factors affecting response to chemotherapy (3)
- Drug
eg dose intensity, scheduling, cell-cycle specificity - Tumour
eg resistance, stage, anatomic site, blood supply - Patient
eg drug tolerance, renal, hepatic function
Drug related factors (4)
- PK (ADME)
- drug distribution to the tumour microenvironment
- MOA (cell cycle specificity)
- combination therapy
Combination therapy to overcome __ (3)
- Sensitivity
- tumours may be non-responsive at normal clinical achievable doses - Toxicity
- avoid the use of high doses cos use lower dose of each drug compared to monotherapy - Resistance
Desirable characteristics for combination therapy (6)
- Each agent must have >20% response rate when used alone
- Different dose limiting toxicities
- prevent additive toxicity - Should not antagonise each other
eg vinca alkaloids & taxanes - Each agent should be given in a dose equivalent to that used when monotherapy
- Different pharmacological action
- increase MOA, increase chance of eliminating tumours - Increase overall intensity of therapy
Tumour related factors (5)
- Tumour growth kinetics
- Tumour size
- Site of tumour
- sanctuary sites (eg testis & CNS) - Tumour vascularisation
- large tumours have central necrosis due to poor blood supply - Tumour cell heterogeneity (resistance)
- Goldie-Coldman hypothesis
- developing resistance is a multi-step event
Small tumours
- high growth rate
- chemotherapy most active against
- early detection/screening impt so can initiate chemotherapy agents early
Large tumours
- most cells are not proliferating & less likely to be killed by chemotherapy agents
Increasing tumour size & risks (3)
- greater probability of metastasis
- greater probability of drug-resistant cells
- poor drug distribution
Patient related factors (5)
- Patient’s overall health status
- Immunocompetency
- Organ function
- Treatment history
- cumulative dose limiting toxicities - Patient’s age
Patient’s overall health status measurements (2)
- Karnofsky Performance Status Criteria (subjective measure)
- increase percent means increase function/activity - ECOG Performance Status
- grade 0-4
- increase grade means increase disability
Immunocompetency (3)
- impaired cell-mediated immunity is a poor prognistic factor
- disease progression & anti-cancer therapies collectively impair immune system
- use of immunosuppressants for minor ailments also impair immune system eg corticosteroids
Organ function (5)
- most chemotherapy are eliminated hepatically or renally
- determine drug clearance and possible accumulation of toxicities
- functional monitoring is essential before & during treatment
- monitor for signs & symptoms of toxicity
- empirical dose adjustment
Treatment history (2)
- Cumulative toxcities
- toxicities from past treatment have cumulative toxicities
eg myelosuppression leading to life-threatening aplasia
- affects dose & scheduling of chemotherapy to avoid life-threatening aplasia
- *Resistance
- if recent chemo use and still relapse, likely resistance development
- tumour factors NOT patient factors
Patient’s age (4)
- myelosuppression recover more slowly among older patients
- controversial issues regarding resilience to chemotherapy in elderly patients
- can initiate chemo if overall health ok
- consider concomitant diseases
Curative vs Palliative (3)
- intense short term ADR
- long term ADR
Curative
- reduction in intensity are accepted only for compelling reasons
- intense short term but reversible toxicity is acceptable if there are no other alternatives
- long term permanent toxicities to be avoided where possible
Palliative
- aim is to improve quality of life
- intense short term toxicity is undesirable
- long term toxicities are generally not a consideration (avoid)
Palliative chemotherapy (3)
- control residual disease/metastases &
- reduce existing cancer symptoms (eg pain, obstruction)
- may be used together with surgery &/or radiotherapy
Neoadjuvant vs Adjuvant chemotherapy
Neoadjuvant
- administered before surgery to “debulk” the tumour, reducing the extent & disfigurement of surgery
- eradicate micrometastases
Adjuvant
- to eradicate any residual micrometastases & prevent them from growing into clinically evident disease
- used together with surgery/radiotherapy (after)
Factors affecting choice of chemotherapy agents (4)
- Types of tumours, stage & rate of growth
- Patient factors (age, organ function, health status)
- Costs
- Availability
Treatment evaluation (5)
- Response rate
- Duration of response
- Duration of survival
- Toxicities associated with treatment
- Impact on quality of life
Response rate measurement (2)
- reflects the % of patients who had tumour regression following therapy
- types :
1. Complete Response (CR) - for at least 1 month
2. Partial Response (PR) - at least 50% decrease of measurable tumour
- no new area of disease & no evidence of progression
3. Disease Progression (DP) - increase >25% of measurable tumour
4. Stable Disease (SD)
5. Overall response rate (CR+PR)
6. Clinical benefit (CR+PR+SD)
Duration of response measurement (2)
- time from the first documentation of response to the recurrence or progression of the tumour
- types :
1. Time to disease progression
2. Disease free interval time
Measurement of survival
Overall survival rate
- proportion of patients surviving for a defined period of time
Measurement of toxicities associated with treatment
Common Toxicity Criteria (CTC)
- grade 0 to 5
- 0 means non-severe
- 5 means most severe (death releated)
Karnofsky Performance Status (2)
- 0%
- 20%
- 60%
- 100%
- measure of the level of activity of which the patient is capable of
- range from 0-100%
0% means dead
20% very sick, require hospitalisation & active supportive treatment
60% require occasional assistance
100% means normal function
ECOG Perfomance Status
- measure of level of activity of which the patient is capable of
- grade 0 to 4
0 means fully active (normal function)
4 means completely disabled
Hematological toxicities
- objective signs (eg neutropenia)
- clear guidelines to withhold or delay treatment
Non-hematologica toxicities
- subjective signs & symptoms
- individual threshold varies & determine withhold or delay treatment
Measurement of impact on quality of life (2)
- Karnofsky Performance Status
2. ECOG Perfomance Status
