Dosing Done Right a Review of Common Chemotherapy Calculations

How is dosage of cancer therapy calculated for adults?

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Introduction

Cytotoxic chemotherapy agents take a steep dose response human relationship and a narrow therapeutic index. The bulk of cytotoxic chemotherapy doses are individualised for each patient and about ordinarily calculated based on the patient'southward body surface area (BSA), renal function or weight. BSA has been shown to correlate with cardiac output, total blood volume as well as renal role. Diverse formulae exist to estimate BSA using height and weight with the Mosteller and Dubois formula'south existence those near commonly used.^[ane] ^[2] For medications that are cleared through glomerular filtration such equally carboplatin, area under the curve (AUC) dosing is used because there is a strong correlation betwixt carboplatin clearance and creatinine clearance.

Doses of biological therapies including monoclonal antibodies and oral targeted therapies may be calculated using the BSA or patient weight. Fixed dosing, where the same dose is used regardless of patient parameters, is more commonly used with oral targeted therapy.

Testify Summary

There is no evidence to back up the use of 1 formula for calculating BSA over another.^[3] The Mosteller formula is the easiest to remember and summate and therefore may be more than widely used in clinical practice. It too provides an accurate estimation of BSA in underweight, normal weight and overweight/obese patients and is applicative to children.^[iv] ^[one]

Although it is common do that dose adjustments are made if the patient's weight varies past greater than 10% during treatment, in that location is no evidence that this should be undertaken.

Overweight/obese patients

Consensus recommendations suggest that overweight/obese patients with curable diseases can exist under-dosed if the BSA is capped to forestall toxicities. Dosing co-ordinate to the actual body weight of the patient may achieve amend outcomes with documented condom toxicity profiles.^[5] ^[three] ^[half-dozen] ^[7] Although these recommendations were made for patients with solid tumour malignancy it is reasonable to extrapolate this in the haematology malignancy setting.

Consensus guidelines are available to inform dosing of cytotoxic chemotherapy used in conditioning regimens for autologous or allogeneic transplant in the setting of obese overweight patients.^[8]

Stock-still or flat dosing

Stock-still dose or flat dose prescribing does not take into account body size or organ role and is rarely used for cytotoxic chemotherapy. The 2012 American Guild of Clinical Oncology (ASCO) skillful console recommends consideration of fixed dosing for a few select cytotoxic agents in the context of specified protocols and tumour types (e.one thousand. vincristine, bleomycin and carboplatin). On the basis primarily of neurotoxicity concerns, vincristine is capped at a maximum dose of two mg when used as part of the CHOP [cyclophosphamide, doxorubicin, vincristine, prednisolone and CVP (cyclophosphamide, vincristine, prednisone)] regimens.^[three]

Glomerular filtration rate (GFR) dosing

In the bulk of circumstances dose calculations for carboplatin are based solely on renal part. Generally, glomerular filtration rate (GFR) is estimated using serum creatinine and calculated according to the Cockcroft-Gault equation. Other methods used to judge the GFR include the Modification of Diet in Renal Disease (MDRD) study equation and the Chronic Kidney Illness Epidemiology Collaboration (CKD-EPI) equation. The latter is more than widely reported automatically by clinical laboratories every fourth dimension a creatinine is measured. Although the MDRD and CKD-EPI equations have been shown to be more accurate, the majority of recommendations for dose adjustments in renal harm were made based on the assumption that the GFR was estimated using the Cockcroft-Gault equation. This formula is normally applied to summate creatinine clearance (CrCl) prior to dosing.

Limited studies take been done in the obese population with regards to estimates of CrCl using the Cockcroft-Gault equation. Excess fatty oftentimes causes a reduction in daily creatinine urine excretion per kg of body weight, and tin sometimes overestimate CrCl.

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Recommendations

Consensus-based recommendation
Doses of cytotoxic chemotherapy should be dosed co-ordinate to the bodily body weight and/or BSA of the patient where there is a curative intent, unless a protocol specifies otherwise. Obesity alone should non be used equally a rationale for capping BSA for chemotherapy dosing (Hunter et al, 2009; Griggs et al, 2012; Field et al, 2008). Methods for computing BSA should be standardised and the aforementioned method used by all clinicians at the institution. Many electronic programs (e.thou. an oncology data system or computerised prescribing systems) permit the auto-calculation of BSA using the elevation and weight and for CrCl using the Cockcroft-Gault equation. Almost available systems take configurable calculators embedded, thereby allowing each institution to select which formula they wish to utilize. Special consideration should be given to calculating doses for individuals with poor performance status or those with co-morbidities which may bear on tolerability and drug clearance. Dose capping or dose reductions fabricated in this setting should be based on the individual patient parameters and clinical prove (Gurney, 2002; Gurney, 2006). All doses that deviate from a standard evidence-based protocol should exist clearly documented. Specialised autologous or allogeneic transplant settings should adopt specific dosing policies related to the conditioning regimens used. Consensus guidelines are available (Bubalo et al, 2014). Renal function should be used when computing doses for renally excreted chemotherapy such as carboplatin. The Cockcroft Gault formula is the most accepted interpretation of CrCl for chemotherapy dosing. In obesity, actual body weight should be used in the calculation of CrCl via the Cockcroft-Gault method to obtain more reliable measures of renal function. The original Cockcroft-Gault formula to estimate GFR used bodily body weight, as no patients were obese. Therefore by using bodily torso weight for obese patients in the Cockcroft-Gault calculation, information technology can upshot in an overestimate of the GFR and a higher than needed carboplatin dose. The re-weighing of the patient during therapy to recalculate the BSA and subsequent doses will depend on local policy, treatment intent and the extent of weight change. Dose adjustment should be made according to the presence or absenteeism of toxicity, as well as changes in other factors that may affect medication elimination such equally renal and hepatic role and concomitant medication. All dose reductions that deviate from a standard evidence-based protocol should exist clearly documented. The checking of the patient'south renal role during therapy with carboplatin to recalculate the carboplatin doses will depend on local policy, treatment intent and the extent of renal part change.

Consensus-based recommendation

Doses of cytotoxic chemotherapy should be dosed co-ordinate to the bodily body weight and/or BSA of the patient where there is a curative intent, unless a protocol specifies otherwise. Obesity alone should non be used equally a rationale for capping BSA for chemotherapy dosing (Hunter et al, 2009; Griggs et al, 2012; Field et al, 2008).

Methods for computing BSA should be standardised and the aforementioned method used by all clinicians at the institution. Many electronic programs (e.thou. an oncology data system or computerised prescribing systems) permit the auto-calculation of BSA using the elevation and weight and for CrCl using the Cockcroft-Gault equation. Almost available systems take configurable calculators embedded, thereby allowing each institution to select which formula they wish to utilize.

Special consideration should be given to calculating doses for individuals with poor performance status or those with co-morbidities which may bear on tolerability and drug clearance. Dose capping or dose reductions fabricated in this setting should be based on the individual patient parameters and clinical prove (Gurney, 2002; Gurney, 2006). All doses that deviate from a standard evidence-based protocol should exist clearly documented.

Specialised autologous or allogeneic transplant settings should adopt specific dosing policies related to the conditioning regimens used. Consensus guidelines are available (Bubalo et al, 2014).

Renal function should be used when computing doses for renally excreted chemotherapy such as carboplatin. The Cockcroft Gault formula is the most accepted interpretation of CrCl for chemotherapy dosing. In obesity, actual body weight should be used in the calculation of CrCl via the Cockcroft-Gault method to obtain more reliable measures of renal function. The original Cockcroft-Gault formula to estimate GFR used bodily body weight, as no patients were obese. Therefore by using bodily torso weight for obese patients in the Cockcroft-Gault calculation, information technology can upshot in an overestimate of the GFR and a higher than needed carboplatin dose.

The re-weighing of the patient during therapy to recalculate the BSA and subsequent doses will depend on local policy, treatment intent and the extent of weight change. Dose adjustment should be made according to the presence or absenteeism of toxicity, as well as changes in other factors that may affect medication elimination such equally renal and hepatic role and concomitant medication. All dose reductions that deviate from a standard evidence-based protocol should exist clearly documented. The checking of the patient'south renal role during therapy with carboplatin to recalculate the carboplatin doses will depend on local policy, treatment intent and the extent of renal part change.

Practise bespeak
The calculation for BSA should be standardised and the aforementioned method used by all clinicians at the institution. The use of printed tables and slide-rules for the adding of BSA is an out-dated practice and should be avoided. For carboplatin, if an estimated GFR based upon measured serum creatinine is used in the Calvert formula, consideration should be given to limit the maximal GFR for the calculation to 125 mL/min (U.S. Nutrient and Drug Administration, 2015). This recommendation does not use if the GFR is straight measured. Limited studies have been performed in the obese cancer population with regards to estimates of CrCl using the Cockcroft-Gault equation. As the Cockcroft-Gault formula overpredicts CrCl in obesity, lean or ideal body weight may be used to right for excess fatty. In obesity, ideal torso weight should be considered in the calculation of CrCl when using the Cockcroft-Gault method to obtain more reliable measures of renal function. Straight measurements of GFR using radiolabelled EDTA must be considered for patients receiving adjuvant or college dose carboplatin. Calculated doses may require 'rounding' to enable delivery of a measurable dose for both parenteral and oral doses and will depend on local practice (e.g. doxorubicin 53.85 mg could be rounded to 54 mg). Dose adjustments should exist made according to the presence or absence of toxicity, equally well as changes in other factors that may affect medication elimination such every bit renal and hepatic function and concomitant medication. Dose adjustments are less unremarkably required with monoclonal antibodies. Weight-based dosing is simply used for a few cytotoxic chemotherapy agents including cladribine, melphalan and arsenic. This is largely based on how medicines were initially developed. In the absenteeism of data suggesting increased toxicity for underweight or obese individuals receiving weight-based dosing, doses should be based upon actual torso weight.

Practise bespeak

The calculation for BSA should be standardised and the aforementioned method used by all clinicians at the institution. The use of printed tables and slide-rules for the adding of BSA is an out-dated practice and should be avoided.

For carboplatin, if an estimated GFR based upon measured serum creatinine is used in the Calvert formula, consideration should be given to limit the maximal GFR for the calculation to 125 mL/min (U.S. Nutrient and Drug Administration, 2015). This recommendation does not use if the GFR is straight measured.

Limited studies have been performed in the obese cancer population with regards to estimates of CrCl using the Cockcroft-Gault equation. As the Cockcroft-Gault formula overpredicts CrCl in obesity, lean or ideal body weight may be used to right for excess fatty. In obesity, ideal torso weight should be considered in the calculation of CrCl when using the Cockcroft-Gault method to obtain more reliable measures of renal function.

Straight measurements of GFR using radiolabelled EDTA must be considered for patients receiving adjuvant or college dose carboplatin.

Calculated doses may require 'rounding' to enable delivery of a measurable dose for both parenteral and oral doses and will depend on local practice (e.g. doxorubicin 53.85 mg could be rounded to 54 mg).

Dose adjustments should exist made according to the presence or absence of toxicity, equally well as changes in other factors that may affect medication elimination such every bit renal and hepatic function and concomitant medication. Dose adjustments are less unremarkably required with monoclonal antibodies.

Weight-based dosing is simply used for a few cytotoxic chemotherapy agents including cladribine, melphalan and arsenic. This is largely based on how medicines were initially developed.

In the absenteeism of data suggesting increased toxicity for underweight or obese individuals receiving weight-based dosing, doses should be based upon actual torso weight.

(Hunter et al, 2009) ^[five] ;(Griggs et al, 2012) ^[three] ;(Field et al, 2008) ^[vi] ;(Gurney, 2002) ^[9] ;(Gurney, 2006) ^[ten] ;(Bubalo et al, 2014) ^[eight] ;(U.S. Food and Drug Administration, 2015) ^[11]

References

↑ ^1.0 ^1.1 Mosteller RD. Simplified calculation of torso-surface area. N Engl J Med 1987 Oct 22;317(17):1098 Available from: http://www.ncbi.nlm.nih.gov/pubmed/3657876.
↑ Du Bois D and Du Bois East. A formula to estimate the approximate expanse if elevation and weight be known. Curvation Intern Med 1916;17:863–71.
↑ ^3.0 ^3.1 ^three.ii ^three.3 Griggs JJ, Mangu PB, Anderson H, Balaban EP, Dignam JJ, Hryniuk WM, et al. Advisable chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology clinical practise guideline. J Clin Oncol 2012 May 1;thirty(13):1553-61 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22473167.
↑ Verbraecken J, Van de Heyning P, De Capitalist W, Van Gaal 50. Body surface area in normal-weight, overweight, and obese adults. A comparing study. Metabolism 2006 Apr;55(iv):515-24 Bachelor from: http://www.ncbi.nlm.nih.gov/pubmed/16546483.
↑ ^5.0 ^five.1 Hunter RJ, Navo MA, Thaker PH, Bodurka DC, Wolf JK, Smith JA. Dosing chemotherapy in obese patients: bodily versus assigned torso surface area (BSA). Cancer Treat Rev 2009 February;35(1):69-78 Bachelor from: http://www.ncbi.nlm.nih.gov/pubmed/18922643.
↑ ^6.0 ^vi.ane Field KM, Kosmider Due south, Jefford M, Michael 1000, Jennens R, Greenish M, et al. Chemotherapy dosing strategies in the obese, elderly, and sparse patient: results of a nationwide survey. J Oncol Pract 2008 May;4(3):108-13 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20856612.
↑ Sparreboom A, Wolff AC, Mathijssen RH, Chatelut E, Rowinsky EK, Verweij J, et al. Evaluation of alternating size descriptors for dose calculation of anticancer drugs in the obese. J Clin Oncol 2007 October 20;25(thirty):4707-13 Bachelor from: http://world wide web.ncbi.nlm.nih.gov/pubmed/17947717.
↑ ^eight.0 ^8.1 Bubalo J, Carpenter PA, Majhail N, Perales MA, Marks DI, Shaughnessy P, et al. Conditioning chemotherapy dose aligning in obese patients: a review and position argument by the American Society for Blood and Marrow Transplantation do guideline committee. Biol Blood Marrow Transplant 2014 May;20(5):600-16 Available from: http://world wide web.ncbi.nlm.nih.gov/pubmed/24462742.
↑ Gurney H. How to summate the dose of chemotherapy. Br J Cancer 2002 April 22;86(8):1297-302 Available from: http://www.ncbi.nlm.nih.gov/pubmed/11953888.
↑ Gurney H. Developing a new framework for dose calculation. J Clin Oncol 2006 Apr 1;24(x):1489-90 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16574997.
↑ FDA (US Food and Drug Administration). Carboplatin dosing. [homepage on the internet]; 2015 Nov [cited 2016 Sep]. Available from: http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm228974.htm.

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Dosing Done Right a Review of Common Chemotherapy Calculations

How is dosage of cancer therapy calculated for adults?

Introduction