Chemotherapeutic agents are well-investigated and beneficial medications, but extra caution must be taken when handling these products given their lower therapeutic index and lower margin of safety as compared to other drug classes, which makes them more prone to cause harm when an error occurs. Because these drug products may lead to serious toxicities even at approved dosages and administration schedules, they are included on the Institute for Safe Medication Practices’ (ISMP) list of high alert medications.¹ Adding to the complexity of chemotherapy, the dose, dosing interval/frequency, and route of administration tends to vary depending on the type and stage of cancer, and multiple agents may be used at the same time, thereby increasing the chance for error and harm. Cisplatin, for example, is administered in a variety of different doses and dosing intervals depending on the treated cancer (bladder, ovarian, testicular, cervical). Calculating the proper dose based on patient body size and laboratory results such as creatinine levels further complicates the prescribing process.

With improved supportive therapies such as antiemetics, colony-stimulating factors, and bone marrow and stem cell transplantation, chemotherapy regimens have become increasingly intensive and complex, making extra precautions essential.^2,3 These concerns have prompted oncology pharmacists and other cancer specialists to recommend that health care organizations improve their medication-use systems specifically to lower the risk of errors involving antineoplastic medications.^4-7 

Computer-assisted Standardization
Numerous process improvement measures have been suggested to improve oncology patient outcomes, including use of standardized order forms, manual and computerized pharmacy review of orders, and attending co-signature for chemotherapeutic agents.^{4, 8-9} Of these methods, only CPOE has been formally evaluated and shown to reduce errors.¹⁰ The Institute of Medicine estimates that at least one quarter of all medication-related injuries are preventable and recommends electronic prescribing through a CPOE system as one way to reduce medication errors and patient harm overall.11 Medication errors related to poor handwriting, use of unsafe abbreviations (including chemotherapy drug name abbreviations, acronyms, and nicknames, such as CPT-11 for irinotecan), and incorrect placement of decimal points and zeros, also may be reduced through the use of CPOE. 

Order standardization and use of preprinted order sets have been linked to a reduction in the number of medication errors, while serving to simplify the order process and reduce rework for pharmacists, nurses, and physicians.¹² Well-designed, standardized medication order forms lower the risk of error by organizing treatment information in a clear, consistent, and uniform format.³ Standardized, preprinted order sets should be easily accessible from a computerized database or website on a health care organization’s intranet, and these sets can serve as a precursor to templates for order sets developed in CPOE.

Evidence-based Pathways 
At the University of Pittsburgh CancerCenter, we utilize evidence-based pathway order sets and protocols first developed by our oncologists in 2005. These arose from a need to ensure quality and consistency of care across our network of almost 200 providers at more than 30 cancer center sites. The order sets are organized by type of cancer (bladder, breast, colorectal, lung, lymphoma, head and neck, melanoma, pancreatic, prostate, etc). Our oncologists’ pathway order sets and protocols have been expanded into a nationwide fee-paid service with 33 separate disease committees, comprising expert oncologists along with medical administrators from all participating practices, who meet quarterly to update the pathways’ clinical content with new evidence, user feedback, unique patient scenarios, and even drug shortages information.¹³ As an example, the format of a pathway order may include the following:

• Name of drug regimen and schedule (eg, FOLFOX, every 14 days)
• Treatment plan
• Diagnosis
• Parameters for treatment (eg, platelets, absolute neutrophil count, magnesium level)
• Antiemetic and premedication orders (oral and/or intravenous) including schedule (eg, day 1 and day 15)
• Chemotherapy/medication orders including dose per unit, final dose, and schedule 
• Additional orders or lab work 
• Adjunct medications (eg, pegfilgrastim)
• Patient allergy and demographic information (height, weight, body surface area [BSA])

Advantages of CPOE Systems
CPOE systems provide many of the same safety and convenience features as preprinted order forms, but there are additional advantages as well. CPOE can simplify prescribing by ensuring that all of the required aspects of the order are in place for the physician, eliminating misreading of written prescriptions, guiding the physician as to safe and appropriate choices, and utilizing forcing functions. CPOE also eliminates the need for intermediaries to interpret and transcribe orders into a manual database, reducing the risk of introducing prescribing errors at that stage, and it offers an efficient means for simultaneously disseminating orders to various providers. 

CPOE also can provide online information about drug dosages and administration schedules, both of which can be updated from a central location, as well as identify drug dosages and administration schedules that are outside preset limits via dose-checking algorithms. (The alerts require pre-setting a warning dose level for each chemotherapeutic agent in a given regimen.) It can also alert users when medications that may interact are prescribed. CPOE software can perform dose calculations, including patient-specific BSA, lean body weight, area under the curve, and estimation of creatinine clearance, and it can maintain automated scheduling of multiple-day treatments, repeated treatment cycles, and laboratory tests. With programmed alerts, CPOE also can lower the risk of selecting contraindicated routes for administration, such as intrathecal administration of vincristine.³

The Road to Standardization 
ISMP developed its Guidelines for Standard Order Sets to help organizations ensure that the elements of safe order communication have been followed when designing paper-based or electronic order sets. The guidelines primarily focus on medication orders within order sets, but also cover general aspects related to the design, approval, and maintenance of all standard order sets. ISMP recommends using its checklist to guide the design and evaluation of standard order sets before granting approval for use.¹⁴ The American Society of Clinical Oncology (ASCO) is another excellent resource for developing oncology practice guidelines, as are the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, which offer a broad spectrum of recommendations for treatment by cancer site, prevention and detection, supportive care, and related issues.^15,16

Standardized forms should be developed in collaboration with all participants in the medication use process, including oncologists, pharmacists, pharmacy admixing technicians, laboratory technicians, nurses, and administrators. To ensure staff acceptance and utilization, it is important to develop a consensus on the components of standardized chemotherapy orders, such as the premedications, diluents, supportive care measures, dosing strategies, and chemotherapeutic agents, before instituting new order sets. 

Establishing Chemotherapy Practice Guidelines 
Clinical practice guidelines are systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances.¹⁷ In developing chemotherapy practice guidelines, the following points should be considered: dose ceilings, route restrictions, dosing calculations, dosage adjustments, hydration, and antiemetic orders. Dose ceilings/limits may be used for a single dose, to establish the maximum amount that may be administered during a specific time interval, or to establish the maximum administration rates for intravenous medications in general. Limits also should be established for the maximum amount of an antineoplastic drug that may be administered during one treatment course or cycle and, when appropriate, the maximum amount of drug that may be administered to a single patient within his or her lifetime.⁴ 

Dosing calculations/guidelines also should be included as part of the practice guideline to ensure proper dose per unit (eg, mg/m2, million units/m2) of the chemotherapeutic agent ordered. The various routes by which each drug may be administered should also be defined; bortezomib, for example, may be administered subcutaneously or intravenously. Furthermore, when administering a chemotherapy agent intravenously, it must be determined whether a bolus or continuous infusion is more appropriate. The rate of infusion is important because some agents, if given too slowly, can increase the risk of adverse effects, and vice versa. Guidelines should assist with dose determinations (eg, weekly paclitaxel 80 mg/m2) allowing for dose adjustments based on organ function (hepatic, renal, cardiac) and antineoplastic agent. Standardized hydration and antiemetic orders should be developed as part of each practice guideline as well.

Unique Chemotherapy Issues
Traditional chemotherapy is unique in that it is not usually prescribed for daily treatment. Rather, it is generally administered on a weekly, biweekly, 21-day, monthly, or longer basis, and some chemotherapy regimens are scheduled on specific days of a monthly cycle. This schedule presents distinct challenges for a CPOE system. With this in mind, the CPOE system should be programmed so that it will be able to recognize specific scheduling parameters and alert the prescriber if chemotherapy is ordered too soon. 

Some practitioners prefer to cap BSA calculations for chemotherapy doses, despite ASCO guidelines suggesting otherwise.18 Thus, a CPOE-driven system should provide the practitioner with the ability to cap the BSA if she or he chooses to. The system also should establish a reasonable range in which a BSA would be expected to fall, depending on the patient population. This can help to prevent unnecessary alerts during order entry.

Another unique aspect of chemotherapy is the prospect of lifetime cumulative doses for certain medications. Several chemotherapeutic agents (eg,anthracyclines and bleomycin) have recommended lifetime maximum doses. The CPOE system should be able to indicate when a patient is nearing or has reached his or her limit.

The administration of chemotherapy requires monitoring of laboratory values in order to determine whether a treatment can be given on schedule, must be dose-reduced yet still given on schedule, or needs to be held until counts recover. Therefore, the CPOE system should include alerts for laboratory values that are out of range, as well as trends from previous laboratory results. CBC, differential and platelet counts, as well as liver and renal function tests should all be included, as dose reductions or dose holds are necessitated for many chemotherapy agents based on decreased platelet count, decreased neutrophil count, decreased renal function (eg, platinum agents, pemetrexed) or decreased liver function (eg, taxanes, vincristine). 

Value of Forcing Functions 
Forcing functions are techniques that help reduce or eliminate the possibility that a medication can be prescribed, dispensed, or administered in a potentially lethal manner. Within CPOE programs forcing functions can be configured to prohibit the ordering of medications if key information, such as allergies or patient height and weight, has not been entered, preventing the user from proceeding until the required information is provided.² CPOE systems also can be programmed to prevent improper administration routes, such as allowing only the intravenous route to be selected for vincristine administration. 

Forcing functions also can require all necessary auxiliary components of an order to be accounted for in order to proceed. For example, if a physician orders ifosfamide, the system would automatically include required hydration orders and mesna as part of the order, and would not finalize the order until the physician confirmed all components. Furthermore, using forcing functions can help ensure selection of the correct unit of measure, such as with interferon alpha-2b, which is ordered not in units, but in millions of units. Enabling double checks of these functions by physicians, nurses, and/or pharmacists should be built into CPOE system functionality.

Minimize Chemotherapy Cost and Waste
Drug cost and waste, especially in light of numerous chemotherapeutic drug shortages, is always a concern. At UPMC, we encourage rounding to the whole number for chemotherapeutic agents that are dosed greater than or equal to 6 mg/m²2. For example, a dose that calculates to 35.2 mg would be rounded to 35 mg. If a chemotherapeutic agent were dosed at 5 mg/m² or less, we recommend rounding to the nearest tenth of a milligram. We also encourage rounding to the nearest vial size if it falls within 5% of the actual dose, which can help reduce unnecessary costs and drug waste. With this in mind, CPOE programs should have built-in fields that prevent a dose from being ordered as 1,900.4 mg, for example. Utilizing these capabilities can help decrease the likelihood of dosing errors involving decimal points. A CPOE-driven system should ideally capture this type of data and suggest doses based on vial size, or at the very least, provide pharmacy with the capability to round doses without calling or otherwise interrupting the prescriber. A rounded dose should fall within the percentage range established by the institution’s policies. 

CPOE in Clinical Trials
Clinical trials play a large role in many university-based teaching hospitals. These trials are typically detail oriented and follow a template reviewed by an investigational drug services team. For these drugs, the CPOE system must be able to capture data such as required laboratory values, timing of pharmacokinetic blood draws, appropriate premedications, the sequence in which chemotherapy is to be given, the length of a particular infusion, and whether the IV line needs to be flushed after the infusion is completed. The CPOE system also needs to alert staff as to which products are provided by the study and which products are commercially supplied. Most important, CPOE-driven systems should be able to capture data such as patient-specific permanent dose reductions inherent to a specific protocol.

Further Improvements with CPOE
Looking ahead, there are a number of improvements that we would welcome in forthcoming CPOE software versions. One benefit would be to ensure that orders link and update automatically; if the date and time is changed on one order, the dates and times on future orders would be changed accordingly for a course of therapy. Another potential improvement would be the reduction of unnecessary alerts in order to prevent alert fatigue. In addition, being able to see all of the relevant information at one time (as you would on paper) would help in performing double checks such as height, weight, laboratory values, previous chemotherapy doses administered, and current chemotherapy order. Increasing the capabilities of the CPOE system to allow custom views would be beneficial as well. 

As high-alert medications with a low therapeutic index, chemotherapy must be used with extra caution, making standardized order sets based on evidence-based practice guidelines essential to ensuring patient safety. Use of CPOE systems provides an extra layer of safety that has been demonstrated to reduce the chance for error, although one must be proactive and anticipate new types of errors that may be created. Chemotherapy prescribing has many nuances that differ from other drug classes, and these must be carefully considered in the standardization process for CPOE. 

References

1. ISMP’s list of high alert medications. Available at: http://ismp.org/Tools/institutionalhighAlert.asp. Accessed March 4, 2013.
2. Cohen MR. Preventing medication errors in cancer chemotherapy. In: Cohen MR, ed. Medication Errors. 2nd ed. Washington, DC: APhA; 2007:445-468. 
3. ASHP guidelines on preventing medication errors with antineoplastic agents. Am J Health Syst Pharm. 2002;59:1648–1668.
4. Cohen MR, Anderson RW, Attilio RM, et al. Preventing medication errors in cancer chemotherapy. Am J Health Syst Pharm. 1996;53:737–746. 
5. Attilio RM. Caring enough to understand: the road to oncology medication error prevention. Hosp Pharm. 1996;31:17–26. 
6. Beckwith MC, Tyler LS. Preventing medication errors with antineoplastic agents, part 1. Hosp Pharm. 2000;35:511–523.
7. Committee on Quality of Health Care in America. Crossing the Quality Chasm: a New Health System for the 21st Century. Washington, DC: Institute of Medicine, National Academy Press; 2001.
8. Opfer KB, Wirtz DM, Farley K. A chemotherapy standard order form: Preventing errors. Oncology Nursing Forum. 1999;26:123-128.
9. Fischer DS, Alfano S, Knobf T, et al. Improving the cancer chemotherapy use process. J Clin Oncol. 1996;14:3148-3155. 
10. Beckwith MC, Tyler LS. Preventing medication errors with antineoplastic agents, part 2. Hosp Pharm. 2000;35:732–747.
11. Bates DW, Leape LL, Cullen DJ, et al. Effect of computerized physician order entry and a team intervention on prevention of serious medication errors. JAMA. 1998;280:1311-1316.
12. Harvey C. Collaborative development of a standardized order form for orthopaedics. Orthopaedic Nursing. 1990;9:34-37. 
13. Via Oncology Pathways. http://viaoncology.com. Accessed March 18, 2013.
14. ISMP’s guidelines for standard order sets. Available at: http://www.ismp.org/Tools/guidelines/StandardOrderSets.asp. Accessed March 4, 2013.
15. American Society of Clinical Oncology. Available at: http://www.asco.org. Accessed March 3, 2013.
16. National Comprehensive Cancer Network. Available at: www.nccn.org. Accessed March 4, 2013.
17. Institute of Medicine. Clinical Practice Guidelines: Directions for a New Program. Field MJ and Lohr KN (eds.). Washington, DC: National Academy Press;1990:38.
18. Griggs JJ, Mangu PB, Anderson H, et al, for the American Society of Clinical Oncology. Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2012;30:1553-1561.

Joanne G. Kowiatek, RPh, MPM, FASHP, is an oncology pharmacist at the University of Pittsburgh Medical Center (UPMC) CancerCenter and an adjunct assistant professor at the University of Pittsburgh School of Pharmacy in Pittsburgh, Pennsylvania. Joanne received a BS in pharmacy from the University of Pittsburgh School of Pharmacy and a masters of public management in health systems from Carnegie Mellon University’s H. John Heinz III College School of Public Policy and Management. She also is director-at-large on the ASHP Section for Inpatient Care Practitioners Executive Committee. She has authored numerous journal articles and book chapters contributing to medication safety literature.

Marie C. Kelly, BS, RPh, is an oncology pharmacist at the University of Pittsburgh Medical Center (UPMC) CancerCenter in Pittsburgh, Pennsylvania. Marie received a BS in pharmacy from the University of Pittsburgh.

Potential Failure Points in Electronic Chemotherapy Ordering

• Prescribing privileges: At the UPMC CancerCenter, only attending oncologists and oncology fellows are permitted to sign chemotherapy orders. Unique electronic signatures designated to prescribers are essential to ensuring that orders are signed by appropriate personnel. Keep in mind, physicians may share their electronic signature with a nurse or physician assistant, so such behavior must be heavily discouraged. The focus of education at this stage should be on guaranteeing that an electronic signature confirms that the specific physician has actually reviewed and signed off on the order.
• Capturing custom orders: Infusion times and diluent volumes are decisions typically made by pharmacists. The CPOE system should be able to prevent overwrites of custom infusion times, as minimum and maximum volumes and infusion rates should be predetermined. 
• Entry error: Typographical errors can occur even in an electronic system. A height can easily be transcribed incorrectly; for example, a height of 5 feet 7 inches accidentally transcribed as 57 inches. There needs to be a form of double check to prevent such transcription errors.