Principles of cancer treatment Flashcards
What is TD
Doubling Time: Time taken for tumour to double its mass, varies among different tumour
Two main pathways of metastasis
- Blood
2. Lymphatic system
Describe the Mechanism of Tumour cell metastasis
- Tumour cell release lytic enzyme, causing basement membrane to dissolve
- Invade and move through defect due to increased motility and decreased cell-cell adhesiveness
- Tumour then bind to basement membrane through mediation of altered receptors on cell surface
Two key properties of tumour growth
- Growth is logarithmic
2. Once detectable, tumour appears to grow quickly
Factors affecting Tumour Growth Kinetics
- Vasculature
- Presence of other cell populations
- Space restrictions
- Necrosis
On the Gomperzian Growth Curve, what affects the slope of the curve?
- Ratio of cell division to cell loss
- Growth fraction
- TD
What is “Silent Cancer”
Tumour at undetectable levels but rapidly growing
Common metastatic sites
- Liver
- Lung
- Lymph
- Bone
- Brain
- Skin
- Adrenal Glands
Goals of Cancer Therapy
- Curative
- Maintain quality and duration of life
- Sx relief, if uncurable
- Clinical Trials for experimental therapies
Characteristics of Ideal Cancer Treatment
- Safe, effective, discriminating (like abx)
- Actions only limited to cancer cells
- Few SE
- Curative
List the three types of cancer treatment and briefly describe their purpose
- Surgery: Debulking
- Radiation
- Chemotherapy: For systemic or disseminated diseases, including micrometastases, as adjunct to surgery/radiotherapy and palliation
Dose-limiting factor of radiation therapy. Hence what is its effectiveness to different tissue?
Damage to normal tissue
- Early effects to rapid dividing tissues
- Late effects in organs
Describe the three basic principles of Cancer Chemotherapy
- Drug kills via first order kinetics (constant proportion)
- Drugs have narrow TI: Must balance between toxic and efficacy
- Combination chemo can be used to improve tx outcome
Distinguish between resistance and relapse in Chemotherapy treatment
- Resistance: Chemotherapy initially effective, but tumour cell levels never fall below clinical detection
- Relapse: Tumour cell levels fall below limit of detection. When chemotherapy stops, tumour levels bounces back to detectable levels
What do each of the principle of Cancer Chemotherapy imply about cancer treatment?
- Constant proportion killing:
- Treatment when tumours are small gives better result
- Chemo greatest effect on actively dividing cells
- Repeat treatment cycle - Narrow TI:
- Decreasing tolerance and challenges to cure, extend life and palliate sx
- Always know intent of treatment and hence adjust the intensity
Advantages and Disadvantages of Combination Chemotherapy
Advantages:
- Increase killing within acceptable toxicity
- Broadened coverage
- Slow emergence of resistance
Disadvantages:
- Multi toxicities = more discomfort
- Complicated to administer
- Impact of dose effect (e.g. titration of dose = get intended effect?)
- More Expensive
Describe the Protocols concept in Chemotherapy
- Different cocktails of chemo for different tumours
- Efficacy established via clinical trials
- Different centres have different protocols for treatment
How is dosing of chemo usually expressed and why is it expressed that way
Almost always: unit weight/body surface area (BSA) (e.g. 60mg/m2)
Reason: BSA is more closely correlated with cardiac output, which determines blood flow to liver and kidney, and subsequently influences drug elimination
Formula for BSA
Sqroot (Weight x Height / 3600)
A Chemo Protocol orders for:
- IV Doxorubicin 60mg/m2, day 1
- IV Cyclophosphamide 600mg/m2, day1
- Repeated every 21 days
What are the two reasons
on why repeated doses spaced so far apart?
- Achieve optimal therapeutic benefit with minimal toxicity
2. “Drug rest” to allow normal cells to recover
Define dose intensity. What are the ways to intensify dosing regimen of a chemo protocol?
Dose intensity is the amount of drug given per unit time, and has profound influence on treatment outcome.
Ways to intensify:
- Reduce interval between repeated doses
- Increase the dose of each administration
What are the factors affecting the selection of Chemotherapy Regimen?
- Histological documentation of tumour type
- Stage of disease
- Prognostic variables
- Patient-related variables
- Toxicities
- Risk vs Benefits
Describe the general algorithm for treatment that leads to selection of therapeutic regimen for cancer
- Determine histological dx, tumour staging, prognostic variables
- Identify tx and determine benefit
- Assess comorbid conditions and psycho-social environment
- Determine tx risk
- Assess risk vs benefit
- Select therapeutic regimen
The three broad factors that affects response to chemotherapy
- Drug
- Tumour
- Patient
Describe the Drug-related factors that affect response to chemotherapy
- Drug PK: distribution to tumour microenvironment
- MoA and cell cycle specificity
- Different effect in combination chemotherapy
What problems are combination chemotherapy used to overcome?
- Sensitivity: overcome non-responsiveness of tumours at clinically achievable monotherapy doses
- Toxicity: avoid high doses to minimise toxicity
- Resistance: Inherent genetic instability leads to non-random mutation conferring resistance
[Slides 45-47 for illustrations]
What are some mechanism of resistance to drugs developed by tumour cells? Name one example of each mechanism
- Decrease cellular uptake/ increase drug efflux: MTX
- Increase ability to repair DNA: DNA damaging drugs
- Decreased drug activation: Ara-C
- Increased drug degradation: Ara-C
- Alternate biochemical pathways: Ara-C
What are some desirable characteristics of the chemo agents used in combination therapy?
- Must be effective (>20% response rate)
- Different dose-limiting toxicities
- Should not antagonise each other
- Give in a dose equivalent to that used when agent is given alone
- Have different pharmacological action
List the Tumour-related factors that affect response to chemotherapy
- Tumour growth kinetics
- Tumour size
- Site of tumour and tmour vascularisation
- Tumour cell Heterogeneity - Resistance
Describe how Tumour Growth Kinetics affect the response to chemotherapy
- When tumour is small with high growth fraction, chemo is most successful
- Highlights the importance of early detection/screening programs
Describe how a large Tumour Size affect the response to chemotherapy
Large tumour means that cells are not proliferating, hence less likely killed by chemo
The larger the tumour:
- Greater probability of metastasis
- Greater probability of drug-resistant cells
- Poor drug distribution to tumour microenvironment due to lack of blood vessels
Describe how the site of Tumour and its vascularisation affect the chemotherapy regimen that will be used
- At Sanctuary sites like CNS at Testis:
- Drug penetration poor
- Require higher dose, or special administration - With tumour at necrotic sites (esp. large tumour):
- Poor vascularisation = difficult for drug to reach tumour
What is the Goldie-Coldman hypothesis?
It describes how tumour cells develop resistance to chemo via random mutation
- Tumour cells are genetically unstable = reporudce inconsistently = clones with different characteristics
- For drug therapy, the tumour cells are “moving target” hence some tumour cells may be resistant
Describe the Patient-related factors that affects the response to chemotherapy
- Overall Health status
- ECOG/Karnofsky Perf Status Criteria help guide treatment decisions
- Chemo attenuated only in deadly toxicities to maintain full anti-tumour activity - Immunocompetency
- Impaired immunity is poor prognostic factor
- Disease progress, chemo & immunosuppressants collectively impair immune system - Organ (Renal and liver func)
- Impaired = reduced elimination of drugs = increased systemic toxicity
- Dose reduction often empirical - Tx history (prior chemo/radio tx)
- Tx history affect major organ toxicity
- Anticancer drug cause cumulative myelosuppression, which is a major dose-limiting toxicity of anticancer drugs - Patient age (controversial)
- To factor concomitant disease
Distinguish between how chemo therapy is used in curative vs palliative
Curative:
- Reduce intensity only for compellling reason
- Intense short term, but reversible toxicity is acceptable
- Long term toxicities avoided if possible
Palliative:
- Improve QoL: Intense short term toxicity undesirable
- Long term toxicity not considered
What is “Neoadjuvant” chemotherapy
- Tx given before surgery to debulk tumour to reduce extent and disfigurement of surgery.
- Also helps eradicate micro-metastases
What is “Adjuvant” chemotherapy
- Systemic therapy
- To eradicate residual micro-metastases and prevent them from growing into clinically evident disease
- Usually used with surgery and/or radiotherapy
What is “Palliative” Chemotherapy
- Systemic therapy to control residual disease/metastases and reduce existing cancer sx like pain and obstruction
- May be used with surgery/radiotherapy
What are other factors affecting choice of treatment between surgery, radio and chemo?
- Type of tumour, stage and rate of growht
- Patient: Age, organ function and performance status
- Cost
- Availability
What are some factors considered in evaluating cancer treatments?
- Response rate
- Duration of response
- Duration of survival
- Toxicities associated with treatment
- Impact on QoL
Describe the parameters of response rate that are involved in the assessment of cancer treatment
- Complete response (CR): Complete disappearance of clinical evi of tumour for ≥1 months with retunr of performance status
- Partial Response (PR): ≥50% decrease in measurable tumour. No new area of disease and progression
- Disease Progression (DP): increase of measurable tumour by >25% (since tx initiation). May have new lesion or tumour-induced death
- Stable disease (SD): Measurable tumour that does not meet any of the above. Tumour does not increase/decrease in size by >25% since tx initiation
What are the equations to calculate response ratethat help assess cancer treatment
- Overall response rate/ Objective response rate = CR + PR
2. Clinical Benefit = CR + PR + SD
What is “duration of response” in assessing cancer treatment?
Time from first documentation of response to recurrence or progression of tumour:
- Time to disease progression
- Disease free interval time
What is the duration of response for patients who had CR?
Disease-free survival time
Describe the parameters that measures survival and are involved in the assessment of cancer treatment
- Survival rate: Proportion of patients surviving for defined time after tx
- Median Survival Rate:
- Time from dx, tx or documented response till time when 50% patients died - Duration of survival: The time that a patient or group of patients lives after specific event
- Disease Free Survival Time: Time from CR till disease recurs, or patient dies w/o evi of disease
Three broad categories of toxicities associated with cancer tx
- Dose limiting toxicity
- Hematological toxicities
- Non-hematological toxicities
What tool or measurement is used to measure toxicities of cancer tx?
Common Toxicity Criteria (CTC) and CTC Adverse Events (CTCAE)
What are the tools to measure baseline performance status of patient, such that toxicities can be compared?
- Karnofsky Performance Status (KPS): In terms of %
- ECOG Performance Status: In terms of Grading
- Both KPS and ECOG can be compared with each other
