Patients receiving 5-FU via continuous infusion have over a 30-fold variability in 5-FU clearance rates, meaning that two patients receiving the same dose could have very different blood levels of this chemotherapeutic agent. A phase III study showed that colorectal cancer patients whose 5-FU was dose adjusted to a target AUC of 20 to 24 milligrams per hour per liter, had higher response rates with less toxicity than patients who were dosed only by Body Surface Area. The OnDose immunoassay was developed as a rapid and reliable method to monitor plasma levels of 5-FU in patients receiving the chemotherapeutic agent via continuous infusion so patients could have their 5-FU doses adjusted based on their own metabolic rate of 5-FU.
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Studies monitoring patients’ 5-FU levels have used different algorithms to try to move patients’ plasma levels into a target range. Some algorithms in the literature use dose adjustments as high as 70 to 150 percent increases in patients with the lowest AUC levels. Our experience has shown that most U.S. physicians using the OnDose assay in colorectal cancer patients are more conservative in their dose adjustments. They most commonly increase or decrease the 5-FU dose by 10 to 20 percent with a 10 percent adjustment being the most common. They often do not adjust the dose if the patient is close to the target range, for example an AUC of 18-19 milligrams per hour per liter or 25 to 27 milligrams per hour per liter, as some variability is to be expected with pharmacokinetic measurements. They may not make a dose adjustment if they have an extreme outlier from previous samples for the same patient but may re-test this patient at the next cycle.
It is very important for the accuracy of the OnDose test that patients be drawn while the patient is at steady state for the 5-FU infusion. Please refer to the OnDose sample handling instructions available at the web address at the bottom of the screen. Myriad personnel are available to train your office staff.
Samples drawn while the pump is running on TKO or KVO will not accurately reflect the AUC as the patient will not be at steady state. The samples must be drawn peripherally as port draws will not accurately reflect the patient’s systemic 5-FU levels, even if the port has been flushed.
In Summary:
The OnDose assay is a rapid and reliable method to monitor plasma levels of 5-FU in patients receiving the chemotherapeutic agent via continuous infusion.
The goal of 5-FU dose adjustment is to get patients closer to the AUC target range of 20 to 24 milligrams per hour per liter.
The physician’s clinical judgment for a specific patient is the most important factor in deciding about dose adjustment for colorectal cancer patients.
Variability Case Study
There are many studies that indicate that patients with higher 5-FU plasma levels respond better to 5-FU treatment for colorectal cancer. It has been shown consistently that 5-FU plasma levels, but not dose, correlate with toxicity and response. A population of patients will vary from 30 to100 fold in 5-FU plasma levels. Due to the wide plasma variability in patients and the narrow therapeutic index of 5-FU, the only way to appropriately dose patients on 5-FU is to measure 5-FU levels and tailor the dose to a specific patient.
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The goal of pharmacokinetic dosing is to bring more patients into a target range where efficacy can be maximized and toxicity is minimized. In Myriad’s clinical experience, patients receiving FOLFOX6 using BSA-based dosing have AUCs that vary from 1 to 69 milligrams per hour per liter. The target range is 20-24 milligrams per hour per liter or 8.7 percent of this initial range. There are many factors contributing to 5-FU levels in patients and there will be some variability in a patient’s measurements over multiple cycles. A patient’s result may vary one cycle to the next if there are changes in liver function, co-morbidities, disease state, drug-drug interactions or other metabolic factors. While pharmacokinetic assays do provide precise measurements, one cannot necessarily expect patients to have their 5-FU levels move in lockstep with dose adjustments because of other biological changes in the patient.
A learning curve can be expected as office staff and physicians adjust to the process of taking this measurement and incorporating it into their practice. It is very important for the accuracy of the OnDose test that each sample be drawn while the patient is at steady state for the 5-FU infusion. Please refer to the OnDose sample handling instructions available at the web address at the bottom of the screen. Myriad Personnel are available to train your office staff.
Samples drawn while the pump is running on TKO or KVO will not accurately reflect the AUC as the patient will not be at steady state. The samples must be drawn peripherally as port draws will not accurately reflect the patient’s systemic 5-FU levels, even if the port has been flushed. The OnDose test is contraindicated in patients on theophylline. Chocolate consumption within 12 hours of the assay may falsely elevate the patient’s OnDose result.
In Summary:
The OnDose assay is a rapid and reliable method to monitor plasma levels of 5-FU in patients receiving the chemotherapeutic agent via continuous infusion for colorectal cancer.
The goal is to use 5-FU dose adjustment to get patients closer to the AUC target range of 20-24 mg·hr/L.
Variability can be a result of patient-specific factors or sample handling issues.
2 Short Sample Case Studies
The following are 2 short sample case studies of the OnDose Testing Cycle as described by Dr. Brian Abbott of Myriad Genetic Laboratories.
Case 1:
In this case, the physician started at the standard FOLFOX6 dose of 2400 milligrams per meters squared. The patient was below the target range. On the next test, the physician increased the dose but the AUC decreased a little bit. While this might be concerning at first keep in mind that results may vary one cycle to the next if there are changes in liver function, comorbidities, disease state, drug-drug interactions or other metabolic factors.
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While pharmacokinetic assays do provide precise measurements, one cannot necessarily expect patients to have their 5-FU levels move in lockstep with dose adjustments because of other biological changes that may be occurring in the patient. Because the patient still was below the target range, over the next 2 cycles the physician continued to slowly increase the dose until the patient consistently stayed in the target range at a dose of 3100 milligrams per meters squared. As you can see, using the OnDose test, this physician was able to give this patient more 5-FU chemotherapy that he would have received under the standard dosing regimen.
Case 2:
Here is a case where the patient was above the target range on a standard FOLFOX6 dose. The physician lowered the dose about 20% to keep the patient in target range. When the patient returned for a 2nd line of treatment in April 2011, the physician again started the patient on the standard FOLFOX6 dose of 2400 milligrams per meters squared. This patient was above the target range. By lowering the dose to 1900 milligrams per meters squared, the physician has been able to keep the patient on 5-FU.
