Principles of Cancer Treatment (Part 2) Flashcards
What is the combination chemotherapy and its uses?
- Using more than one agent to overcome the following problems:
1. Sensitivity: tumours may be non-responsive at clinically achievable doses.
2. Toxicity: avoid the use of high doses
3. Resistance: inherent genetic stability commonly leads to non-random mutation and confers resistance.
Desirable characteristics for combination therapy:
- Agents must be effective (>20% response rate when used alone)
- Agents should have different dose-limiting toxicities
- Agents should not antagonise each other when combined.
- Agents should be given in a dose equivalent to when the drug is given alone
- Agents should have different pharmacological action
- Increase the overall intensity of therapy directed at cancer.
Drug-related factors
Pharmacokinetics: ADME
Drug distribution to site of tumour microenvironment
MOA: cell-cycle specificity
Combination chemotherapy
Tumour-related factors
- Tumour growth kinetics
- Tumour size
- Site of tumour and tumour vascularization
- Tumour cell heterogeneity - resistance
Tumour growth kinetics
- treatment is most successful with in tumours with small tumour burden and high growth fraction
» early detection/screening programs are important
Tumour size
- in large tumours the cells are least likely to be proliferating and hence unlikely to be killed by chemotherapy agents.
- the larger the tumour,
» the greater probability of metastasis
» the greater the probability of drug-resistant cells
» poor drug distribution
Tumour cell Heterogeneity - resistance
Heterogeneity:
- genetically unstable –> reproduce inconsistently, clones have different characteristics
- moving target for drug therapy –> tumour cells resistance
Site of tumour and tumour vascularization
- Sanctuary sites (CNS, testis)
» drug penetration poor, difficult to get a sufficient concentration of chemotherapy agent to destroy cancer cells. - Poor blood supply
» large tumor will have central necrosis (chemotherapeutic agents not effective there)
Patient-related factors
- Patient’s overall health status
- Immuno-competency
- Organ functions
- Treatment history
- Patient’s age
Patient’s overall health status
- ECOG/Karnofsky Performance Status Criteria: subjective measure to guide treatment decisions
- Chemotherapy doses attenuated only in presence of life-threatening toxicities to maintain full anti-tumour activity.
- Goldie-Coldman hypothesis: mutations that favour drug-resistance may be developed over time, resulting in the selection of chemotherapy-resistant cancer clones.
- Mechanisms of tumour cell resistance to antineoplastic drugs include:
» decreased drug accumulation (drug uptake + efflux)
» altered drug metabolism
» increased repair to drug-induced damage
» alteration of drug target
Immuno-competency
- impaired cell-mediated immunity is a poor prognostic factor.
- disease progression, anti-cancer therapies and immunosuppressants can weaken the host’s immune system.
organ functions
- check for renal and hepatic impairment before and during treatment
- dose reduction is often empirical
treatment history
- previous therapies can effect organ toxicity
- myelosuppression is major dose-limiting toxicity
- if toxicity is encountered, reduce dose and lengthen dosing interval.
patient age
- myelosuppression recovers more slowly amongst aged patients
- aged patients may also have concomitant diseases that need to be factored in as well.
Differences in curative vs palliative treatment
Curative:
- reduction in dose intensity is accepted only under compelling reasons (why: main purpose is to cure patient).
- long-term toxicities are undesirable, but intense short-term toxicities that are reversible are acceptable if there is no better alternative.
Palliative:
- intense short term toxicities are not acceptable (why: main purpose is symptom relief)
- long-term toxicities are not even a consideration.
What is:
- neoadjuvant chemotherapy
- adjuvant chemotherapy
- palliative chemotherapy
- systemic treatment given before surgery to debulk the tumour, reducing the extent and disfigurement of surgery. Can help eradicate micromestases.
- systemic therapies that are delivered after the surgery or radiotherapy to eradicate residual micromestases, and prevent them from growing into clinically evident disease.
- systemic therapies that are administered to keep the residual micromestases under control and relieve pain symptoms
How is treatment evaluated?
- Response rate
- Duration of response
- Duration of survival
- Toxicities associated with treatment
- Impact on quality of life
response rate
- reflects the number of patients who had tumour regression following therapy.
- complete response: complete disappearance of all evidence of tumour for at least 1 month, performance status returns.
- partial response: at least 50% decrease of measurable tumour, with no new area of disease or evidence of progression.
- disease progression: increase of measurable tumour by >25%, appearance of new lesion.
- stable disease: measurable tumour that does not meet the criteria for CR, PR or DP. Tumour size does not increase or decrease in size by > 25%.
how is clinical benefit calculated?
by taking the sum of CR, PR and SD
duration of response
- measures time from the first documentation of response to the recurrence or progression of tumour.
» time to disease progression
» disease-free interval time (for patients on CR)
toxicities associated with treatment
- common toxicity criteria
» 24 categories classified by pathophysiology and anatomy.
» grades: severity of the adverse event ranges from 0 (none) to 5 (death related to adverse event) - dose-limiting toxicities (limit the amount of dose given to a patient)
- hematological toxicities
» objective toxicities e.g. neutropenia
» clear guidelines to withhold or delay - non-hematological toxicities
» subjective toxicities e.g. fatigue
» individual threshold varies
Measurement of QoL
A. Kanofsky Performance Status
100%: normal, no complaints, no evidence of disease
60%: requires occasional assistance but is able to care for most of own needs.
20%: very sick, hospitalisation and active supportive treatment necessary
B. ECOG Performance Status
0: fully active, can live as per normal without assistance (KPS 90-100)
1: restricted in physically strenous activity, ambulatory and still can do light or sedentary activities (KPS 70-80)
2: ambulatory and capable of self-care but unable to carry out work activities for 50% and more waking hours. (KPS 50-60)
3: Capable of only limited self-care, confined to bed or chair for more than 50% of waking hours (KPS 30-40)
4. Completely disabled, cannot carry on self-care, totally confined to bed or chair (KPS 10-20)
