The cost of cancer care comprises a significant portion of annual health care expenditures in the US; as the population ages, national outlay for cancer care will rise commensurately. Projections suggest an expansion to $173 billion by 2020, a 39% increase from 2010.1

Recent advances in treatment yield new, often expensive, therapies. Treatment with these agents routinely exceeds $100,000 per year, and it is not unusual for some new therapies to be priced as high as $400,000 per year.2 These high expenses are largely due to the advent of monoclonal antibodies over the last 15+ years; the complexity involved with their synthesis makes monoclonal antibodies expensive to produce.3 To manage these rising expenditures, health systems are seeking to deliver financially efficient care without negatively impacting clinical efficacy.

One important strategy to reduce drug costs is to identify areas of product waste in the medication-use process. Because most anticancer treatments are based on a patient’s body surface area (BSA) or weight, when the calculated dose does not require the entire contents of the drug vial, this can result in costly product waste (oftentimes of preservative-free, single use vials). However, dose rounding can be utilized to prevent much of this problem. Rounding doses to the nearest vial size—when the difference is less than an established percentage—is a critical strategy for reducing drug waste and delivering cost savings.

Advantages of Dose Rounding

Dose rounding helps reduce drug waste and streamline workloads, but its primary benefit is cost savings. A number of retrospective studies have assessed these savings by comparing the calculated dose to the rounded dose.4-8 The difference, or amount of drug wasted, can be calculated based on institution acquisition costs or average wholesale price on a per milligram basis. For example:

• A patient’s calculated dose of ipilimumab is 103 mg
• Ipilimumab is available in 50 mg and 200 mg vials
• The 103 mg dose would require three 50 mg vials, resulting in 47 mg of waste; at an institutional acquisition cost of $17.50/mg, this would result in $822.50 of waste to compound just one dose of ipilimumab
• Rounding the dose to 100 mg would avoid this cost

Other examples of cost avoidance are described in SIDEBAR 1.4-8

In addition to the financial benefits, dose rounding promotes increased efficiency in product preparation and simplifies dose checking. Easily measured amounts and recognizable doses contribute to an efficient workflow.

Oncology Agents Targeted for Rounding

The oncology medications typically assigned to dose-rounding protocols are monoclonal antibodies, cytotoxic agents, and oral chemotherapy.

Monoclonal Antibodies

Dose-rounding monoclonal antibodies can help avoid a sizeable portion of medication costs. One reason for this is that these agents are often dosed on body weight instead of BSA.

Monoclonal antibodies typically have a low volume of distribution, excellent water solubility, and high molecular weight. Therefore, the distribution of immunoglobulins is confined to the intravascular space, with minimal drug reaching the extracellular fluid. The volume of fluid located in the intravascular space does not depend on body weight. Thus, in order to achieve sufficient concentrations, monoclonal antibody dosing should not depend on body weight; this concept supports the rationale of fixed dosing.7

For many monoclonal antibodies, a maximum tolerated dose is not determined or is extremely high, resulting in approval doses being much higher than necessary. This situation has occurred with nivolumab, pembrolizumab, and more recently, subcutaneous trastuzumab:

• Upon product launch, nivolumab was dosed at 3 mg/kg every 2 weeks. Since then, based on pharmacokinetic studies, the dosing was changed to a flat dose of 240 mg every 2 weeks, and most recently, to 480 mg every 4 weeks.9
• Pembrolizumab was initially approved as a weight-based dose every 2 weeks but has since changed to a flat dose of 200 mg every 3 weeks.10
• Genentech has received approval for flat dosing of subcutaneous trastuzumab. Although IV trastuzumab is still dosed based on weight, it is interesting to note that Genentech pursued a flat dose for their subcutaneous product from product launch.11

Based on the pharmacokinetics of these agents, as well as data supporting flat dosing, dose rounding of biologic agents up to 10% is acceptable to most clinicians and prescribers.

Cytotoxic Agents

Traditional chemotherapy is less expensive and has a narrower therapeutic index than monoclonal antibodies. Many institutions have deemed 5% an acceptable threshold to round cytotoxic chemotherapy. However, a Hematology/Oncology Pharmacy Association (HOPA) position statement recommends a 10% dose-rounding level, citing two major factors to support this threshold12:

• To improve patient tolerance and tumor response, standard dose adjustments are usually in the range of 20% to 30%.
• The National Cancer Institute Guidelines for Auditing Clinical Trials13 define a major deficiency as a deviation greater than 10% above or below the intended dose, which suggests that rounding by 10% is rational. In addition, dose rounding all oncologic agents to 10% helps standardize the process for staff.

It is important to note that variability in drug clearance occurs among patients as well as among doses for a single patient. Genetic variability in drug metabolizing enzymes and transporters, pharmacokinetic drug interactions, and organ function impairment also contribute to this variability in drug clearance.7

Evidence suggests that relative dose intensity for cytotoxic chemotherapy ≥0.85 is optimal for therapeutic efficacy.14 US Pharmacopeial Convention standards support the actual amount or concentration of an active ingredient per product label for most anticancer treatments to be ±10%. This standard suggests that labeled and actual product amounts are not expected to produce meaningful physiologic changes with a variance of 10%.4 All of these factors support a 10% threshold for dose rounding of cytotoxic chemotherapy.

Oral Chemotherapy

Most oral chemotherapy dosing is flat based; however, a few agents, such as capecitabine and temozolomide, are dosed based on BSA. Rounding oral chemotherapy requires a different approach than rounding IV chemotherapy, as hazardous pills cannot be safely split to reach a specific dose. Consequently, doses should be rounded to the nearest pill size.

Some oral chemotherapies are available in multiple pill sizes. For example, trifluridine-tipiracil (Lonsurf) is offered in 15-6.4 mg and 20-8.19 mg. The typical dose is 35 mg/m2 twice daily (based on the trifluridine) on days 1 to 5 and 8 to 12 of a 28-day cycle.15 The dose for a patient with a BSA of 2.13 m2 equals 74.55 mg twice daily, which would be rounded to 75 mg twice daily. The patient would take one 15-6.4 mg tablet plus two 20-8.9 mg tablets. For this patient, two different tablet strengths would be needed to complete the dose. However, two different tablet strengths should only be used when it is unavoidable, given that multiple tablet strengths are potentially confusing and increase the risk for medication errors.16

Capecitabine is also available in two different tablet strengths, 150 mg and 500 mg, and has various dosing regimens. A patient prescribed capecitabine in combination with radiation may be dosed at 825 mg/m2 twice daily on each day of radiation treatment. With a BSA of 2.23m2, the calculated dose would be 1,840 mg twice daily (total of 3,680 mg per day). Two scenarios of rounding are possible:

• Round using two different tablet strengths. The patient would take three 500 mg tablets and two 150 mg tablets, for a total of 1,800 mg twice daily
• Only use the 500 mg tablets. The patient would take four 500 mg tablets in the morning and three 500 mg tablets in the evening to equal a rounded dose of 3,500 mg a day

The first scenario results in a 2.2% deviation from the calculated dose, while the second example results in a 4.9% deviation. Although rounding the dose with two different tablet strengths results in less deviation, the patient is at a higher risk of taking the wrong dose. Therefore, the second solution would be most appropriate.

In addition to avoiding confusion for the patient, another benefit of using only one tablet strength is that it eliminates the possibility of multiple copayments.

Exercise Caution

Some doses should not be rounded. For example, patient factors must be considered when deciding whether rounding a dose of an oncologic agent is appropriate. Traditionally, patients are dosed based on a treatment plan weight or BSA; the dose will not change until the patient’s weight or BSA has changed ≥10%. Be careful to identify when a weight or BSA has changed enough that rounding a dose of an oncologic agent results in a 15% to 20% difference.

The intent of treatment is another factor to consider (ie, curative vs palliative). The goal for patients on cytotoxic chemotherapy for palliative intent is to manage the disease with the best quality of life. For these patients, rounding up on a dose by ≥10% may not be in their best interest, especially if they are experiencing or previously have experienced side effects from therapy. In those patients with curative intent, some providers prefer not to round down by 10%, fearing this may impact their outcomes. Moreover, for a patient who struggles to tolerate their chemotherapy and is losing weight, rounding up by 8% to 10% on a cytotoxic agent may not be a good option for the patient.

These discussions are important to consider when working with the health care team to draft specific language for a dose rounding policy. Note that after a dose rounding policy is implemented, some unclear scenarios may still be encountered. When in doubt as to whether it is clinically appropriate to round a dose, contact the prescribing physician.

Side Effects

There is some (albeit limited) evidence that dose rounding does not impact the acute side effects of cytotoxic chemotherapy. For example, one retrospective chart review evaluating the effect of dose rounding up to 5% in patients with breast cancer receiving 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) concluded that there were no differences in acute side effects.17 To date, there are no prospective studies evaluating the safety of dose rounding or any studies comparing efficacy.

Implementing a Dose-Rounding Protocol

To implement a dose-rounding protocol, providers, nursing, and pharmacy staff must be in agreement. A significant number of dose-rounding articles are available to assist in implementing a dose-rounding protocol, and institutions that already practice automatic pharmacy dose rounding can provide guidance. The position statement by HOPA titled Dose Rounding of Biologic and Cytotoxic Anticancer Agents18 is an excellent resource to get started with this process at your institution.

M Health Fairview in Minnesota utilizes a pharmacist-only oncology committee that reviews oncology dose rounding suggestions. Once approved through this committee, changes are vetted by a multidisciplinary group comprising physicians, pharmacy leaders, pharmacists, and nurses. Our dose-rounding protocol (available in SIDEBAR 2) received final approval via this multidisciplinary group and was incorporated within our chemotherapy order policy.

With varying dose rounding clinical knowledge among pharmacists, it is important to use specific language to ensure clarity within the protocol. For example, include information on how to assess dose reductions, the intent of treatment, treating pediatric versus adult patients, and other relevant factors. Although the protocol cannot address every possible scenario, a concise, clear document avoids confusion, variability among staff, and dosing errors.

Conclusion

With health care costs continually increasing—for cancer care in particular—reducing waste and controlling expenditures are ever-present goals for every health system. Rounding oncology doses to the nearest vial or pill size, when the difference is less than the established percentage, can yield substantial benefits, from cost avoidance to increased efficiency and reduced waste.

Sara Moran Smith, PharmD, BCOP, is an oncology clinical pharmacist at the M Health Fairview Maple Grove Cancer Center in Maple Grove, Minnesota. She completed her PharmD at the University of Minnesota College of Pharmacy, a PGY1 residency at University of Minnesota Medical Center, and a PGY2 specialized residency in oncology at M Health Fairview Maple Grove Cancer Center. Sara’s professional interests include education; she is a continuing education coordinator for the Minnesota Society of Health-System Pharmacists and provides education sessions for nursing and pharmacy staff in the cancer clinic.

References

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