Oncology Pharmacology

Despite the advances in cancer treatment, the oncology field still reports the lowest efficacy rates of any of the major medical therapeutic areas.  Cancer is a very complex disease and is in fact not one disease, but rather a broad group of various diseases, which compound the challenges of effective treatment and cure.  This is all the more reason the medical community should utilize the tools available as effectively as possible.

Many of the recent breakthroughs in improving the effectiveness of cancer treatment are a result of “personalized medicine,” which involves tailoring medical treatment to the individual characteristics of each patient rather than the “one-size-fits-all” approach of the past.  Much of the focus in personalized medicine has been placed on understanding a person’s unique molecular and genetic profile.  This “pharmacogenomics” profile can be used to predict what makes patients susceptible to cancer or to predict the most optimal course of treatment.  These are remarkable and clinically significant advancements.  ...Show More

 

Although pharmacogenomics can provide the patient’s tumor genotype to identify the optimal drug for an individual, it cannot define the specific dosage necessary to achieve the optimal systemic blood exposure to provide the best therapeutic effect with minimized side effects.

The current standard of care for dosing patients with chemotherapy drugs is Body Surface Area (BSA).  In this age of personalized medicine, BSA still represents the outdated “one size fits all."  This method of dosing, which takes into account only the patient’s height and weight, was derived in 1916 based upon the study of only eight patients as a means of estimating the conversion of drug doses in animals to human doses.(1)  For lack of any better methodology, BSA was subsequently adapted in the 1960’s to dosing of the newly developed chemotherapy drugs.(2)  However, there is no rigorous scientific basis for the use of BSA with cancer drugs and there is growing scientific evidence that this approach is invalid and does not deliver the best care for cancer patients.(3-9)

Several studies have shown that BSA-based dosing is associated with a high degree of drug blood level variability from one patient to another (“interpatient pharmacokinetic or PK variability”) and is a poor metric of optimal drug exposure.  Many factors besides height and weight impact how individuals absorb, distribute, metabolize and excrete drugs.  These factors may include disease stage, organ function, sleep-wake cycles, age, race, drug-drug interactions, food, interaction with nutritional and herbal supplements, among others.(9)  The overall effect of these factors is a high degree of interpatient PK variability.  For example, the distributions of exposure for 5-fluorouracil (5-FU), a commonly used chemotherapy drug, has been demonstrated to be as much as 30 to 100-fold.  This means that if two patients receive equal 5-FU doses based upon BSA, one patient may have 30-to-100 times the drug level in their bloodstream than the other.

Similar results have been reported with other cancer drugs.  In one study, BSA was found to be marginally effective in controlling interpatient drug blood levels in only 15% of 33 new investigational cancer drugs tested between 1991 and 2001.(5)  Another report found the variation in clearance of the most commonly used chemotherapy agents was between 25% and 70%, and most drugs showed interpatient blood level variability higher than 35%. (See chart below)(4) ...

Studies have also shown a clear relationship between systemic drug exposure and biological effect for many chemotherapeutic drugs.  For commonly used drugs like carboplatin, 5-FU, docetaxel and paclitaxel, the upper levels of exposure to these drugs beyond which unacceptable toxicity occurs have been identified.(10-16)  From these studies, doctors can predict which patients are at risk of suffering serious toxic side effects and which patients should be administered higher drug doses to optimize the effectiveness of their treatment.

 

All these studies underscore the need for an alternative to BSA-based dosing that optimizes drug exposure for each individual patient.  The only reliable way to do this is by actually measuring the patient’s systemic drug exposure while they are receiving therapy.  Since the 1970s, doctors have been using simple blood tests to measure plasma drug concentrations and individualize the dose for each patient to achieve the optimal therapeutic efficacy while reducing the risk of dangerous toxic side effects.  This has been the standard of care with transplantation, antiepileptic and antibiotic drugs for many years.

Chemotherapy drugs ideally fit the profile of drugs that should have PK-guided dose management because there is a demonstrated correlation of drug blood levels to biological effects (treatment, efficacy and toxicity) and these drugs clearly present the risk of dose-limiting toxicity.  The body of clinical evidence to support PK-guided dose adjustment is growing, but some oncologists may argue it is not yet strong enough to demonstrate the benefit of such an approach.  Along these lines, the same question could be posed relating to whether there is rigorous scientific evidence to show that BSA is an effective way to dose a drug.  In fact, the published literature shows that BSA dosing fails to achieve what it is intended to do and that it is merely a bad habit that the oncology community practices as a matter of convenience. 

In this age of “personalized medicine,” it is time for the oncology community to embrace a more accurate method of drug dosing that will provide patients the right drug exposure at whatever dose is required for their best level of care.

 

REFERENCES

 

 

   1.   Du BD, Du Bois EF: A formula to estimate the approximate surface area if height and weight be known. 1916. Nutrition 5:303-311, 1989

   2.   Pinkel D: The use of body surface area as a criterion of drug dosage in cancer chemotherapy. Cancer Res 18:853-856, 1958

   3.   Baker SD, Verweij J, Rowinsky EK, et al.: Role of body surface area in dosing of investigational anticancer agents in adults, 1991-2001. J Natl Cancer Inst 94:1883-1888, 2002

   4.   Felici A, Verweij J, Sparreboom A: Dosing strategies for anticancer drugs: the good, the bad and body-surface area. Eur J Cancer 38:1677-1684, 2002

   5.   de Jonge ME, Huitema AD, Schellens JH, et al.: Individualised cancer chemotherapy: strategies and performance of prospective studies on therapeutic drug monitoring with dose adaptation: a review. Clin Pharmacokinet 44:147-173, 2005

   6.   Hon YY, Evans WE: Making TDM work to optimize cancer chemotherapy: a multidisciplinary team approach. Clin Chem 44:388-400, 1998

   7.   Rudek MA, Sparreboom A, Garrett-Mayer ES, et al.: Factors affecting pharmacokinetic variability following doxorubicin and docetaxel-based therapy. Eur J Cancer 40:1170-1178, 2004

   8.   Saif MW, Choma A, Salamone SJ, et al.: Pharmacokinetically guided dose adjustment of 5-fluorouracil: a rational approach to improving therapeutic outcomes. J Natl Cancer Inst 101:1543-1552, 2009

   9.   Takimoto CH: Maximum tolerated dose: clinical endpoint for a bygone era? Target Oncol 4:143-147, 2009

10.   Bruno R, Hille D, Riva A, et al.: Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer. J Clin Oncol 16:187-196, 1998

11.   Gamelin E, Delva R, Jacob J, et al.: Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: results of a multicenter randomized trial of patients with metastatic colorectal cancer. J Clin Oncol 26:2099-2105, 2008

12.   Gianni L, Kearns CM, Giani A, et al.: Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol 13:180-190, 1995

13.   Joerger M, Huitema AD, Richel DJ, et al.: Population pharmacokinetics and pharmacodynamics of paclitaxel and carboplatin in ovarian cancer patients: a study by the European organization for research and treatment of cancer-pharmacology and molecular mechanisms group and new drug development group. Clin Cancer Res 13:6410-6418, 2007

14.   Jodrell DI, Egorin MJ, Canetta RM, et al.: Relationships between carboplatin exposure and tumor response and toxicity in patients with ovarian cancer. J Clin Oncol 10:520-528, 1992

15.   Miller AA, Rosner GL, Egorin MJ, et al.: Prospective evaluation of body surface area as a determinant of paclitaxel pharmacokinetics and pharmacodynamics in women with solid tumors: Cancer and Leukemia Group B Study 9763. Clin Cancer Res 10:8325-8331, 2004

16.   Capitain O, Asevoaia A, Boisdron-Celle M, et al.: Individual fluorouracil dose adjustment in FOLFOX based on pharmacokinetic follow-up compared with conventional BSA dosing: a phase 2, proof-of-concept study. Clin Colorectal Cancer:11:263-267 2012

 

Publications of Interest

J Clin Oncol. 2012 Nov 1; 30(31):3896-7

J Clin Oncol. 2012 Nov 1; 30(31):3896-7

Body-Surface Area–Based Chemotherapy Dosing: Appropriate in the 21st Century?

Many advancements in the development of anti-cancer drugs have been towards more personalize drugs, however few, if any change has occurred in how we dose.

http://jco.ascopubs.org/content/30/31/3896.full

 
 
 
 
Personalized Medicine

Personalized Medicine