The determination of standardised rounded doses is indispensable for mass production, ensuring quality assurance, and eventually leading to automation of the production. It also allows the management of chemotherapy preparation in a rational way
The adjustment of doses of anticancer chemotherapy drugs to the patient is a common practice. It is established on the narrow therapeutic margin of the cytotoxic agents, with a small variation between the therapeutic and the toxic doses.(1) Moreover, their large intra- and inter-patient variability in pharmacokinetics and pharmacodynamics complicates chemotherapy dosing. To reduce this variability, most of the dosages of anticancer agents are traditionally fitted to the physical surface (body surface area; BSA), expressed in m2, or weight, expressed in kg.
The diversity of active substances and doses prescribed in clinical departments implies that prescriptions are prepared extemporaneously for each patient. However, this individualisation of doses is not always compatible with the requirements of a production in a centralised unit with pharmaceutical responsibility for centres with an important workload. One of the main challenges for these hospital pharmacies is to provide timely preparations of guaranteed quality. A streamlining of doses can help production.
Questioning BSA-based dosing
The practice of calculating chemotherapy doses adjusted to a patient’s BSA has been in place for the past 50 years, albeit without scientific basis.(2) Indeed, it has been questioned in several studies in recent years.(3-6) However, there is still no satisfactory alternative to BSA-based dosing, and the development of recently marketed anticancer drugs continues to be based mainly on BSA.
The realisation that some flexibility, evaluated to be between 5 and 10%, is allowed in the calculation of doses has led to the pragmatic concept of dose banding. For a given drug, doses calculated according to the conventional parameters (physical surface, weight) can be adjusted and find themselves in intervals defined beforehand, corresponding to a unique dose per band, usually the mid-point of the BSA band in which the actual BSA of the patient lies.(7) The concept of dose banding has been initiated in the UK, where it is widely used to provide chemotherapy for oncology in- and outpatients, often through a combination of prefilled syringes.(8)
It can be a support to establish a rationalisation of anticancer drug production, particularly in centres with increased chemotherapy workload, such as the Institut Curie (Paris) and Hôpital Saint-Louis (Paris).(9)
A study of dose standardisation was conducted in these two hospitals, each hospital pharmacy department owning its anticancer drug preparation unit.
The Hôpital Saint-Louis is a university hospital with 398 beds, with the number of chemotherapy preparations estimated at 75,000 per year.
Its activities are mainly oriented towards haematology and general oncology. The Institut Curie is a cancer treatment centre with 227 beds, processing nearly 40,000 preparations of chemotherapy per year. Activities of the main departments are mammary pathology and solid tumours.
A study was conducted in 2007 to determine standardised rounded doses (SRD) for selected drugs. We chose this method of standardisation so as to define a maximum of five to six doses for each drug, presented in a single preparation. The chosen doses have to be frequently prescribed, and correspond to a precise and easy-to-withdraw volume. Dose standardisation was considered interesting in terms of productivity only if the percentage of standardisation was greater than 60%.
Choice of agents
For that purpose, an analysis of doses prescribed for all the drugs used in both hospitals was performed. Clinical trials and children’s prescriptions were not included in our data. Then, in association with the oncologists, we determined for which drug it was advantageous to measure this standardisation in terms of frequency of prescription, stability and organisational interest.
The universality of protocols had to be taken into account. For example, at Institut Curie, one of the most commonly prescribed protocols is FEC (5-fluorouracil, epirubicin, cyclophosphamide). At Hôpital Saint-Louis, most protocols in haematology contain rituximab. Those molecules can all be provided ‘off the shelf’ as prefilled infusion bags (IV bags).
Method of dose determination
An agreement was reached between pharmacy, nursing and medical staff concerning the bands of doses that could be defined as acceptable for every drug, according to the bibliographical and clinical data an the therapeutic window. The variation of ± 5–10 % from the theoretical calculated dose was unanimously approved.
We chose to present our preparations with selected SRD in IV bags ready to administer.
Implementation of SRD was conducted in each hospital:
- Potential chemotherapy drugs were chosen, and SRDs were measured with a degree of flexibility of 5–10%.
- A process from prescription to administration was defined, specific to each hospital.
Evaluations of doses and of new drugs to adapt to the current production need to be conducted regularly, and validated by oncologists.
Electronic prescribing systems, such as our specific prescription software Chimio® (Computer Engineering), need to include this new way of dose adaptation, in order to propose automatically a SRD for the chosen molecules. Then, this dose proposition has to be validated by the prescriber, according to the characteristics of the patient and of the tumour. It has been agreed that, if no justification can be found that SRD has not been chosen, the pharmacist has the right to modify the dose. In case of dose reduction for toxicity, the preparation is manufactured externally through the traditional process.
At Institut Curie, dose standardisation was a first step towards automation of the manufacturing process. A new process dedicated to SRD via an automated filler system was proposed (PharmaHelp prototype).(10) This medical device has been developed for hospital pharmacies to prepare automatically and accurately IV syringes and bags with a high level of autonomy and less human intervention. It comprises a robot integrated in an HEPA ISO 5 air-handling system with a robotic arm performing filling, reconstitution and shaking of vials for dilution in syringes or IV bags. Loading and unloading are the only tasks performed by the operator.
This system was chosen for management of the risk of drug exposure, and to protect technicians from possible musculoskeletal disorders.
In this context of high-level requirements, an automated system coupled with environmental protection could help to improve the hospital pharmacy productivity and profitability with high- level quality control and technicians’ safety. Automation of repetitive and complex tasks requiring vigilance and accuracy could reduce the incidence of errors and relieve operators of repetitive tasks.
Batches of drugs of each dose are manufactured, based on the prescription’s prevision. The calculation of the necessary number of IV bags is made weekly, taking into consideration of the projected schedule of the patients, so as to reduce drug wastage. Each preparation is identified by a number, written on the label. Once controlled, preparations are stored informatically and physically.
At the validation of the prescription by the pharmacist, a preparation of the corresponding drug and dosage, identified by its number, is attributed to the patient. Control of the dispensing is in the hands of a pharmacist before the preparation is sent to the chemotherapy service. To minimise the risk of error, specific training of the staff was organised and controls of the correct attribution of the preparation were added.
At Hôpital Saint-Louis, some preparations of SRD (rituximab) are prepared in batches, with a stability of 30 days (Table 1). The IV bags are then stored and made available when the prescription is made, in a similar manner as described at Institut Curie.
However, for most drugs, the prescription is prepared in SRD. This way, even molecules with short-term stability can present SRDs. For example, doses have been proposed and accepted by the Pharmacy and Therapeutic Committee for bortezomib. Preparation of chemotherapy is made easier with SRD corresponding to a whole number volume, corresponding to the nearest vial size (gemcitabine, rituximab) or function of the syringe graduation (bortezomib). The dose adaptation is made by either the oncologist or the pharmacist. A message on the administration sheet informs nurses that the dose can be rounded.
Staff training is organised regularly so as to present and maintain this dose standardisation method.
In the event of change or cancellation of treatment, the preparation is returned to the pharmacy. If reallocation is permitted, the prepared dose is not wasted and can be used for another patient, provided the conditions of temperature storage are respected. Indeed, no dose adjustment is needed, where the preparation can be either thrown away or reused with a dose adaptation of ±5%.
Implementation of SRD in both anticancer drugs preparation units has been in place for three years. Feasibility of SRD has been confirmed, as selected SRD enable coverage of more than 80% of the production of each hospital. Support of prescribers was seen in both hospitals, including recently appointed oncologists and residents.
This method is not restricted to large hospitals, and we can see that it can be implemented in two different ways: ready-to-use IV-bags, or dose adaptation of the prescription and external preparation.
The determination of SRD is indispensable for mass production, ensuring quality assurance, and eventually leading to automation of the production. It also allows the management of chemotherapy preparation in a rational way, with:
- an increase in production capacity, with an optimisation of the capacity planning of the preparation unit;
- a prospective quality control, and a reduced risk of medication errors and miscalculations;
- a decrease in wastage, with the possibility of a cost-saving reallocation of unused preparations, and
- a reduction in patient waiting time.
- Successful implementation of concept of standard rounded doses has been confirmed in both hospitals.
- It can help to reduce waste in production, and reallocate unused preparations.
- It enables a reduction in patient waiting time in clinical services, and diminishes stress in the production unit.
- Both small and large institutions can benefit from this system.
- DuBois D, DuBois E. A formula to estimate the approximate surface area if height and weight be known. Arch Intern Med. 1916;17:863–71.
- Pinkel D. Cancer chemotherapy and body surface area. J Clin Oncol 1998;16:3714–5.
- Gurney H. Dose calculation of anticancer drugs: a review of the current practice and introduction of an alternative. J Clin Oncol 1996;14:2590–611.
- Reilly JJ, Workman P. Normalisation of anti-cancer drug dosage using body weight and surface area: is it worthwhile? A review of theoretical and practical considerations. Cancer Chemother Pharmacol 1993;32:411–8.
- Sawyer M, Ratain MJ. Body surface area as a determinant of pharmacokinetics and drug dosing. Invest New Drugs 2001;19:171–7.
- Baker SD et al. Role of body surface area in dosing of investigational anticancer agents in adults, 1991-2001. J Natl Cancer Inst 2002;94:1883–8.
- Plumridge RJ, Sewell GJ. Dose-banding of cytotoxic drugs: a new concept in cancer chemotherapy. Am J Health Syst Pharm 2001;58:1760–4.
- Loos WJ et al. Evaluation of an alternate dosing strategy for cisplatin in patients with extreme body surface area values. J Clin Oncol 2006;24:1499–506.
- Pouliquen AL et al. Dose standardisation of anticancer drugs. Int J Clin Pharm 2011;33:221–8.
- Hurgon A et al. PharmaHelp for cytotoxic handling. Hosp Pharm Eur 2010;52:62–4.