Chemotherapy Dosing and Monitoring Flashcards
Why is getting the dose right important?
- Too much; kill patient (toxicity)
- Undertreat, patient dies
»> 20% dose reduction may virtually eliminate an otherwise high complete remission rate by as much as 50%.
What is the most widely used method of dosing chemotherapy? What does it entail?
Body surface area (BSA)
- Based on a patient’s height and weight
- Several formulas, but DuBois and DuBois is most commonly used.
- Patient’s BSA can vary between 1.71 - 1.93 m^2 for the same height and weight w/different formulas.
What is the DuBois and DuBois estimation of BSA based on? What were their findings?
- Based on measuring surface area of 9 cadavers
- SA = (W^0.425 x H^0.725) x 0.007184
- Demonstrated correlation between blood volume, circulating plasma proteins, renal function and BSA.
How accurate is BSA e.g. for cachectic/obese?
- BSA can vary in the same way BMI does; people with the same BSA can have v. different builds
What is Ideal Body Weight?
A weight that is to be healthy for a particular height.
When is IBW used over ABW for BSA dosing?
- ABW (Actual) used normally; unless patient is obese or cachectic (v. thin)
- Would use IBW for these instances
How does treatment intent influence if ABW or IBW is used for BSA dosing?
- May use ABW if treatment intent is curative; no evidence that toxicity is increased.
What are the issues with capping BSA at 2m^2 (and 2.2m^2 in haematology)?
- Risk that obese patients may be undertreated
- Many consultants no longer capping curative regimens; less risk of larger patients relapsing.
What are the disadvantages of using BSA to dose chemotherapy?
- Does not consider effect of renal disease impairment (even if correlation w/renal function)
- BSA is estimated; not accurate (based on rando cadavers)
- Formulae takes no account of obesity/cachexia
- No direct relationship between BSA dosing and drug clearance
- No direct relationship between BSA dosing and outcome
- Rounding occurs during BSA calculation; introducing even more inaccuracy
Why is BSA still used as the standard if there are so many disadvantages?
- Continues to be used as original Phase I and II trials used BSA (despite inaccuracies)
- Starting point for dosing, then adjusted after 1st cycle, based on response, toxicity etc. (usually adjusted down due to S/Es)
What are the causes of variation with chemotherapy dosing?
Individual patient drug handling +/- 15%:
- Pharmacogenetics
- Disease effects
- Hepatic/renal dysfunction
- Co-morbidities
Vial contents +/- 15%:
- Manufacturer may change as hospital looking for cheapest (each one is different)
- Vial type
- Aseptic technique (sharing etc.)
Weight, Height, BSA +/- 10%:
- Shoes
- Clothes
- Time of day (fasting/fed)
- Calibration (scales)
- Method of BSA calculation
Syringe accuracy +/- 5%:
- Manufacturer
- Type
- Size (3ml vs. 50ml)
- Air bubbles etc.
Residual volumes during administration +/- 5%:
- Filter absorption
- Administration set
- Needle
- Practice (inadequate flushing of line after)
When is Area Under Curve (AUC) used to dose chemotherapy?
- To dose carboplatin (alternative to Cisplatin in pts. w/deteriorating renal function)
- Calculates dose based on creatinine clearance; need accurate GFR
What method would you use to calculate GFR to work out AUC dosing?
- Cockcroft-Gault
»> eGFR not sufficient; fine for most renally excreted drugs but not for nephrotoxics; based on a 1.73 m^2 BSA
»> eGFR would not be accurate for obese/cachexic patients
Cockcroft-Gault (for AUC) requires a body weight; when would you use Ideal Body Weight, Adjusted Body Weight and Actual Body Weight?
- Most BSA uses actual body weight
- But, IBW used in nephrotoxic drugs to calculate GFR.
- If actual weight is 30% more than IBW, then used adjusted body weight (v.obese/elderly):
ABW = IBW + 0.4 (actual weight - IBW)
In what patients is it ideal to use IBW in calculating nephrotoxic chemotherapy?
- Patients < 39 years
- BMI > 30
What is the best practice measure of GFR?
Using radiolabelled EDTA/DPTA:
- Patients injected with it
- Bloods taken at 2, 3, 4 hours
- Serine blood tests show how quickly isotope is cleared, providing an accurate measure of GFR.
In what patients should radiolabelled EDTA be used to calculate GFR (for AUC) prior to carboplatin therapy?
- Cachexic
- Obese
- Elderly
- Children
When is anticancer therapy dosed by body weight? Advantages?
- Mostly biologicals (newer) e.g. bevacizumab, trastuzumab etc
- Doses not capped
- Easier to calculate (less risk of error)
- Uses recent, accurate weight
What are the issues with weight-based dosing?
- May under-dose with small body size
- May overdose in large body size (BSA may not necessarily be larger)
»> Use IBW or ABW
When is fixed dose dosing used? Advantages?
- New oral biologicals e.g. TKIs ‘nibs’
- Suitable for drugs w/wide therapeutic window
- Ease of dose preparation
- Reduced cost
- Lower risk of dosing errors
What are the issues with fixed dosing?
- Overdose small body size
- Underdose large body size
(Opposite of weight based dosing)
What does dose banding entail? How are the tables designed?
- Individually calculated doses, placed within different bands
- Predetermined starting dose applied to each band
- Tables designed so that maximum variation between standard dose administered to patient and prescribed dose is < 5%
What are the different dose banding methods availible?
- Linear
- Target
- Logarithmic
What does Linear dose banding entail?
- BSA centered dose banding
- E.g. Capecitabine tablets only availible as 150mg/500mg, patient w/BSA 1.74 m^2 needs a dose of 1000mg/m^2 BD.
What dose prescribed?
»> 1650mg or 1800mg (+/- 3-5%; prescribed dose of 1740mg)
> 1800 mg prescribed (max for BSA)
What does Target dose banding entail?
- Drug centered dose banding, or ‘target dose’ banding
- E.g. rituximab is dosed on BSA< then rounded up/down to nearest band
What does Logarithmic dose banding entail?
- 80% rule for calculating dose bands, e.g. 100%, 80%, 64%, 51.2% rather than 100/80/80 in linear dose banding.
- Not widely used
What are the benefits of dose banding?
- Dose rationalisation/standardising
- Fewer dose calculation errors
- Quicker dispensing through use of pre-prepared doses (pre-prepared syringes/infusions
- Administration of chemotherapy on any chosen day is facilitated
- Rationalisation of demand, with aseptic capacity liberated for more complex chemotherapy and more time for clinical duties
- Reduced waste by re-use of cancelled doses and avoidance of incomplete vial usage during aseptic production
- Use of smaller syringe sizes make bolus administration easier
- Easier processing of dose reductions at short notice
What are the disadvantages of using dose banding?
- Administered dose may vary from BSA calculated dose by up to +/- 5% (but BSA not accurate anyway)
- Up to three syringes needed for bolus dose
- Risks associated with manipulation of multiple syringes
- RSI risk for aseptic operators/nurses administering w/repeated syringe manipulation
- Banded doses may be more expensive (acquisition cost) if outsourced
What are the potential benefits of TDM?
- Cytotoxic drugs fulfil prerequisites for TDM
- May improve clinical outcome and tolerability
- Identifies patients not adhering to patient
- Allows individual dose optimisation
What are the disadvantages of TDM?
- Tumour heterogeneity
- Required drug concentration usually unknown
- Time lag between clinical measurement and effect
- Drugs have overlapping therapeutics and toxic effects
- TDM more complicated in drugs with non-linear kinetics
- Practical or economic considerations; serial samples, training of staff etc.
Why is high dose MTX the only cytotoxic where plasma levels are routinely monitored?
- To ensure MTX is being cleared (rather than to check a therapeutic range has been reached)
- Folinic acid given until MTX is < 0.2 micromol/L
How does MTX work?
- Folate antagonist (inhibits DHFR)
- THF is active form of folic acid required for purine and thymidylate synthesis; folate acid reduced to THF by DHFR.
- MTX inhibits DHFR.
Why is folinic acid (leucovorin) given, 24 hours after MTX?
- ‘Rescue’ to block unwanted S/Es (damage to healthy tissue)
- Overcomes metabolic blockade caused by MTX
- May block the effects of MTX if given too soon after; as it does not require DHFR for activation.
> Hydrate patient too
> As well as maintaining urine pH > 7 with sodium bicarbonate infusions (prevent crystal formation; COO- salt form in body)
Why is chemotherapy given in cycles? When is it appropriate to start the following cycle?
- Scheduling based on effects of cytotoxics on normal and tumour cells
- Rapidly proliferating cells much more sensitive to damage: bone marrow, mucosal epithelial cells of the oropharynx, gut, bladder, hair follicles
- Bone marrow and epithelial lining cells have large capacity for tolerating and recovering from damage
- Normal cells recover from damage within 2-3 weeks; thus successive course given 3 weekly to allow health cells to recover
- Next course not given until damage from previous drug exposure repaired
When does maximum damage from cytotoxic chemotherapy occur during a cycle of chemotherapy? When is the WCC nadir?
- Few days-1 week after each treatment
- Nadir WCC: 7-10 days
- Normal cells: recover over 2-3 weeks
How are toxicity grades outlined?
Patient is assessed for toxicities before each cycle; scored Grade 1-5.
1) Mild; asymptomatic or mild symptoms, clinical or diagnostic observations only; intervention not required
2) Moderate; minimal, local or non invasive intervention indicated; limiting age-appropriate ADL (activities of daily living)
3) Severe or medically significant but not immediately life-threatening; hospitalization (or prolonged) indicated; disabling; limiting self care ADL
4) Life-threatening consequences; urgent intervention required
5) Death related to Adverse Effects
What considerations need to be made re. Renal Function and chemotherapy?
- Nephrotoxic/renally excreted drugs; calculate CrCl or GFR measurement (EDTA)
- Check CrCl prior to each cycle
- Cisplatin; even if renal function okay, patient is pre-hydrated, urine output monitored carefully
> Switch to carboplatin if declining renal function - Individual SPCs advise dose reduction
What is the pre-hydration routine required for Cisplatin treatment?
- Patient gets 1L of saline over 1hr, needs to pass > 100 ml urine.
- If this doesn’t happen; 500 ml saline over 30 mins, 100 ml mannitol 10%
- If urine output still not adequate; do chemo another day.
How does a patient’s Full Blood Count (FBC) influence chemotherapy treatment?
- FBC and differential checked 24 hours prior to next cycle
- Review Hb, Plt, and ANC
- If Hb low = blood transfusion
- If platelets < 30; platelet transfusion (otherwise delay chemo)
- ANC low; delay chemo until > 0.5, 1.0 or 1.5 depending on protocol (consider GCSF; granulocyte-colony stimulating factor with next cycle)
What does GCSF do? When and how is GCSF used?
- Granulocyte-colony stimulating factor
- Significant increase in peripheral neutrophil count
- Avoids treatment delay in patients receiving curative chemotherapy (reduce dose instead of adding GCSF in palliation)
- Not administered within 24 hours of chemotherapy; risk of paradoxical myelosuppression
- Commenced after 48 hours
- S/Es; bone pain
- ANC nadir occurs earlier, recovers faster w/GCSF
When is liver function monitored w/chemotherapy?
- Hepatotoxic chemo (6 mercaptopurine)
- Hepatically-cleared chemo (doxorubicin, docetaxel)
What needs to be considered re. LFTs and chemotherapy?
- Damage more likely when higher doses used
- Criteria for dose reduction not always clear
- Consider deranged LFTs when treating primary or secondary tumours in liver
- Abnormal LFTs due to tumour; should improve following chemo
What are the two classes of cardiotoxicity possibly caused by cytotoxics?
Patients develop heart failure:
- Type 1; irreversible
- Type 2; reversible
What does Type 1 cardiotoxicity entail? Risk factors?
Irreversible:
- Caused by anthracyclines (doxorubicin, epirubicin)
Risk factors:
- Female
- Age
- Rapid administration (lower risk to infuse over 2-3 days w/elastomeric device)
- Exceeding cumulative lifetime dose
- Concomitant mediastinal RT
»> Can occur at any time during treatment.
What does Type 2 cardiotoxicity entail? Risk factors?
Reversible:
- Newer agents e.g. Trastuzumab (Herceptin)
- Risk increases when given with concomitant anthracyclines
How is cardiotoxicity risk from cytotoxic therapy managed?
- Pre-treatment echocardiogram (ECHO)
- Caution/CI if heart failure (ECHO regularly during treatment)
- Calculate lifetime cumulative dose if relapse
