THE STRUCTURED STORAGE OF ONCOLOGICAL

CHEMOTERAPEUTIC REGIMENS

Contribution to Standardization of Therapeutic Procedures in Current Oncology

D. Klimes

, L. Dusek

, M. Kubasek

, J. Novotny

, J. Finek

and R. Vyzula

Institute of Biostatistics and Analyzes, Masaryk University, Kamenice 126/3, Brno, Czech Republik

Department of Oncology, General Teaching Hospital, Prague, Czech Republic

Charles University Prague, Medical Faculty Pilsen, Pilsen, Czech Republic

Masaryk Memorial Cancer Institute, Brno, Czech Republic

Keywords: Cancer Chemotherapy Protocols, Antineoplastic Combined Chemotherapy Regimens, XML, Clinical

Database.

Abstract: The aim of the chemotherapeutic regimens (CHR) digitalization project is the proposal of a universal

structure and creation of a publicly accessible database of contemporary CHR as a universal utility for the

communication and evaluation of contemporary and newly defined clinical schedules in anti-tumor

chemotherapy. After analysis of contemporary anti tumor CHR a standard XML structure was proposed,

which enables the recording of simple CHR from the field of chemotherapy in solid adult tumors, and also

has the potential of recording the complex treatment protocols in the field of paediatric oncology. The

resulting XML documents were saved on a web server. A publicly accessible CHR database was

constructed. There were a total of 130 XML documents with definitions of individual CHR in the first

phase. Linked to this data store, three examples of web applications were added to demonstrate the potential

uses of this newly created database.

1 INTRODUCTION

Chemotherapy, along with surgery and radiotherapy

is an irreplaceable part of the clinical treatment of

oncological illnesses across nearly all diagnoses. To

be more exact, we can define the term of

chemotherapy as encountered in this article. It is the

administration of individual preparations or

combinations of preparations from the anatomical-

therapeutic-chemical group (ATC) L01, which are

anti-tumor preparations. This ATC group currently

consists of nearly a hundred generic preparations,

which are divided into 5 basic groups: Alkylating

agents (L01A), Antimetabolites (L01B), Plant

alkaloids and other natural products (L01C),

Cytotoxic antibiotics and related substances (L01D)

and Other antineoplastic agents (L01X). Whether

these preparations are in practice applied either

separately in monotherapy or in combination, we

refer to them as a chemotherapeutic regimen (CHR).

The more complicated plans for the application of

cytostatics are classified in paediatric oncology as

treatment protocols. Standard CHR are based on

clinical studies and are published in the oncological

journals (Goldberg et al., 2004) (Henderson et al.,

2003) (Citron et al., 2003) and subsequently in

national or international guidelines (NCCN, 2006)

(CLS JEP, 2005).

However, CHR are not merely a list of applied

cytostatics in administered doses; the definition of a

CHR has its own basic rules, which are however not

strictly defined anywhere. The main features of

CHR include: doses of cytostatics are defined most

often according to the surface area of the patient's

body or their weight. CHR are applied in cycles, i.e.

defined time segments of the treatment are repeated

several times. There can be one or more repeated

segments. The days of application are identified

relative to the first day of each cycle (example Cycle

1- Day 1, Cycle 1- Day 8). These features are in

practice routinely used (see Figure 1).

148

Klimes D., Dusek L., Kubasek M., Novotny J., Finek J. and Vyzula R. (2008).

THE STRUCTURED STORAGE OF ONCOLOGICAL CHEMOTERAPEUTIC REGIMENS - Contribution to Standardization of Therapeutic Procedures

in Current Oncology.

In Proceedings of the First International Conference on Health Informatics, pages 148-154

 SciTePress

FEC chemotherapy

Cyclophosphamide 75 mg/m PO days 1-14

Epirubicin 60 mg/m IV days 1 & 8

5-Fluorouracil 500 mg/m IV days 1 & 8

With cotrimoxazole support.

Cycled every 28 days for 6 cycles.

Figure 1: An example of CHR clinical definition (NCCN

The aforementioned structure is frequently used,

however not standardized, as to prevent a wider use

of information technology. The vendors of a hospital

information system can create a special application

module for chemotherapy with a specific, internal

data structure or chemotherapy data is stored only as

a sequence of applications of cytostatics without

specific details. This situation hinders on the one

hand fast electronic transmission of new CHR and

the general intercommunication between computer

applications in this field, and on the other hand the

more advanced use of technology, for instance in the

field of the assessment and adherence to standard

CHR in clinical practice. A possible solution is the

creation of a structured data store of current CHR,

which will mirror current clinical guidelines and

which will be freely accessible to both clinics and

HIS providers. This article describes the proposed

structure of such a data store and the experience

gained during its construction. The practical usage

of such a database of CHR is demonstrated with the

example of a web portal, whose components are web

applications which use the CHR database as its

datasource.

2 METHODS

Preliminary analysis of problems showed that the

construction of a structured database of CHR calls

for certain steps:

1) The proposal of the structure of CHR

2) The unique identification of standard CHR

3) The digitalisation of current standard CHR

CHR can be considered as a type of structured

document, which is why the XML language was

chosen for its recording. Standard XML offers a

workable computational structure. In addition, it also

provides tools for the internal validation of

structures (XML schema) and tools for transforming

documents into different, more user-friendly

formats, for example HTML pages (XSLT). The

proposed XML structure of elements and attributes

was developed dynamically through the analysis of

clinical definitions of standard CHR for individual

oncological diagnoses. The source of the definitions

was the National and International oncological

guidelines (NCCN, 2006) (CLS JEP, 2005) and the

internal source of Masaryk memorial Cancer Institut,

a specialised hospital for the treatment of

oncological diseases in the Czech Republic. The

template for CHR was modelled using XML

schemes, which enabled the definition of individual

elements and attributes. The mandatory/optional

properties and frequency of repetition of elements

are defined by the maxOccurs and minOccurs

indicators.

2.1 Header of CHR

The created XML structure of CHR consists of two

parts. The first deals with the identification of CHR

and the possibility of its use in oncological diagnosis

(header). An example of this header is shown in

figure 2.

<name>AC(Fisher)</name>

<sysname>(1;60.0;mg/m2;iv)A+(1;600.0;mg/m2;i

v)C&21

</sysname>

<purpose>adjuvant</purpose>

</diagnosis>

Figure 2: An example of CHR header definition.

The header contains the element name which

was used for the clinical identification of CHR. This

name was adopted either directly from clinical

guidelines or from clinical identification in the

information system of MMCI. These clinical names

do not guarantee uniqueness and do not adhere to

any strict rules. On the other hand the element

sysname was added to the individual definitions of

CHR on the basis of their internal structure. The

detailed principles of their creation are described

below.

The diagnosis element lists the individual

oncological diagnoses that each individual CHR can

treat. This is a complex element, which contains the

following nested elements. The code for diagnoses is

introduced according to the international

classification ICD-10 in same named nested

elements. The element line defines the CHR which

is suitable (or approved) for specific lines of

treatment.

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The element purpose specifies whether a CHR is

designed for adjuvant or palliative treatment. The

elements line and purpose can, within the one

element diagnosis, occur repeatedly in cases where

the CHR is intended for more lines or for both basic

purposes of treatment. In cases where the CHR is

used for more diagnoses, the whole complex

element Diagnosis is repeated.

2.2 Body of CHR

The second part of the structure describes the

administration of given CHR (body). A standard

CHR was divided into the following components

 The name of administered cytostatics

 Dosage of individual cytostatics

 Units of doses

 Method of administration

 Day relative to cycle of administration

of cytostatic

 Duration of one cycle in days

 Total of completed cycles

Primarily proposed scheme for the body of the

CHR is presented in figure 3.

<group>

<id_group>1</id_group>

<drug>

.......

<drug>

.......

<drug>

</group>

<group>

<id_group>2</id_group>

……….

</group>

Figure 3: The main frame of CHR body definition.

The element interval indicates the duration of

one cycle of chemotherapy in days. The length of

one cycle can be defined as the number of days

between day D1 on one cycle and D1 on the

following cycle. The actual length of the last cycle

can only be determined from the last defined day of

administration and cannot be compared with the

length of the preceding cycles.

The element noc (number of cycles) shows the

total of applied cycles. This parameter is limited by

clinical guidelines to a small number of CHR. These

guidelines often merely provide a recommendation

for the repetion of cycles. In practice the number of

applied cycles is decided by the actual state of health

of the patient. In cases where details were not

explicitly known, the value of this element was set

to 0.

The complex element drug describes the

application of individual cytostatics within the

framework of one cycle of chemotherapy. Since

many cytostatics are applied in CHR, the element

drug is referred to as a recurrent element. The

element drug encapsulates the nested elements for

labelling cytostatics, their dosage, day of

administration and method of administration. As

soon as we try to identify individually applied

cytostatics, the problem of their individual

classification arises. Existing practice is to cite the

full generic name of the cytostatic, which in certain

cases involves the brand name of the medication.

The ATC codes of identification of cytostatics are

not used in clinical practice, however they are ideal

for computer processing. We therefore decided to

include in the XML structure both an element for the

generic name of cytostatics (name) and an element

for the ATC code (ATC). The element name can be

inserted for each cytostatic repeatedly with the

attribute lang for various language versions of

classification. For the purpose of the systematic

naming of CHR (described below) the element abbr

was also defined for the abbreviated names of

cytostatics.

Doses of cytostatics, units of dosage of

cytostatics, method of administration and relative

day of administration were included within the

complex element administration, whose title was

shortened to adm for practical reasons. The element

dose was defined for the dosage of cytostatics as a

real number, for units of dosage the enumerative

element unit, for the method of administering the

enumerative element mode and for the day of

administering the whole number element unit,

respectively the two whole number elements

start_day and end_day.

In anti tumour chemotherapy, the dosage of

cytostatics is most commonly defined by the

calculation of the surface area of the patient or by

their weight. For this reason the element

unit was

defined with the values mg/m

and mg/kg.

Carboplatin has special dosage, where the dose is

defined in AUC. The resulting dose of this drug is

calculated depending on the laboratory value

parameters creatinine clearance (CrCl) according to

the formula:

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dose(mg) = target AUC (mg/ml/min) * (CrCl +25)

(ml/min)

Two basic methods of administering cytostatics

(modes) are used, per oral and intravenous

administration. More detailed categorization can be

considered, for instance distinguishing between

intravenous administrations according to the length

of infusion. In the basic proposal there is the

difference between bolus administration and

infusion. For example in the case of the regimens

FOLFOX 4 and FOLFOX 6, which are used in the

treatment of colorectal carcinoma, it is necessary to

differentiate between the bolus dosage of

fluorouracil from its subsequent longterm infusion.

The element mode can thus include the values iv, iv-

bolus and po.

Day of administration is in clinical practice

presented as Dx, where x is the consecutive number

of days from the administration of the first

preparation in a cycle. Individual cytostatics can be

repeatedly administered within a cycle, either on

chosen days (e.g D1, D8) or daily in the course of an

appointed time period (e.g D1-D14). For the first

variant, the element day can be repeated within the

complex element adm, and in the second variant

there are, in place of the element day, two elements

start_day and end_day. An example of the complex

element drug is illustrated in figure 4.

<drug>

<name lang="cz">Cyklofosfamid

</name>

<name lang="eng">Cyclophosphamide

</name>

<adm>

</adm>

</drug>

Figure 4: An example of the complex element drug.

For ‘multigroup’ regimens such AC+paclitaxel

(see figure 5) it was necessary to extend the

presented concept.

Doxorubicin 60 mg/m IV day 1

Cyclophosphamide 600 mg/m IV day 1

Cycled every 21 days for 4 cycles.

Followed by

Paclitaxel 175-225 mg/m by 3 h IV infusion

day 1

Cycled every 21 days for 4 cycles.

Figure 5: An example of multigroup CHR (NCCN Clinical

For this type of CHR another encapsulating

structure was added to the XML scheme. This took

the form of the specific complex element group,

which contains all the defined elements of the body

of the CHR and can be repeated. For the

identification of groups, the element id_group was

added which contains the consecutive number of the

group. For multigroup CHR it is necessary that the

element noc must not be zero, at least for each group

except the last.

2.3 Systematic Naming of CHR

To prevent duplication in the database of CHR, a

concept was sought after, which would ensure the

individual identification of each of the stored CHR.

The identification of CHR used in clinical practice

seemed unsuitable, because as often happens, one

CHR has more than one name, or one name refers to

more than one CHR.

A unique standard naming of CHR was inspired

by Logical Observation Identifiers Names and

Codes (LOINC). LOINC is a structured

classification of laboratory methods (Huff et al.,

1998). There is a systematic name for each item (in

this example the laboratory method) consisting of

individual components which the method uniquely

refers to. In the case of LOINC, the names of

laboratory methods include the components,

property, timing, system precision and method.

Similarly, it is possible to create a unique

identification system of CHR. The following

requirements were necessary to be taken into

account within the proposals for the rules for the

systematic creation of naming of CHR:

 The naming has to be unique

 The naming must be automatically generated

from definitions of the CHR

 All key components of the scheme must be

coded into the name

 The name must remain "human readable"

The schematic name is created according to the

following syntactic rules:

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 Administered drugs are classified with a unique

abbreviation

 Drugs are alphabetically sequenced according to

abbreviations and are divided by the symbol

plus (+)

 After the listing of the drug the duration of

cycle in days is added after the symbol(&)

 For every drug, the following items are defined

in round brackets separated by a semicolon (;)

The first entry in the brackets is the day of

administration. It can be in the form of a number (1),

a list of numbers separated by commas (1, 8) or an

interval (1-14). The second entry is the dosage of the

medication. The third entry is the abbreviated name

for the method of administration. The fourth entry is

the unit of dosage.

Abbreviations used for cytostatic medications are

summarized in Table 1.

Abbreviations used are parts of the proposal for

the standardization of structures of CHR, because

currently the standard for the abbreviated

identification of cytostatics has not been found (on

the webpages of NCI (NCI Drug Dictionary

National Cancer Institute, 2005) only recommended

abbreviations can be found and all the well known

synonyms for given preparations). Clinically

established abbreviations are often diagnosis-

specific, for example cisplatin is listed under the

letter P in CHR such as BIP or BEP, in the regimen

M-VAC it is classified under the letter C, which is

however in the majority of cases used as the

abbreviation for cyclophosphamide. Due to the fact

that the number of well known cytostatics is very

similar to the number of existing chemical elements

for which two symbols are sufficient for the

abbreviated symbols, a similar concept was used for

the identification of cytostatics. The names of the

most frequently used cytostatics are written in the

table, each is recorded with a NCI abbreviation,

ATC code and proposed two letter identification,

which issues from the generic name of the cytostatic.

For multigroup CHR the concept was further

developed with square brackets enclosing individual

groups. The number of cycles is indicated before the

brackets separated by asterisks (*). Groups are

separated with the symbol +. An example of the

identification of the CHR AC+paclitaxel is

illustrated in figure 6.

Table 1: Summary of most frequently used cytostatic

agents.

Cytostatic

agent

ATC - code NCI

abbreviation*

Used

abbreviation

bevacizumab L01XC07 ? Be

bleomycin L01DC01 BLEO B

busulfan L01AB01 BU, BUS Bu

capecitabine L01BC06 CAPE Ca

carboplatin L01XA02 CBDCA Cb

carmustine L01AD01 BCNU Bc

cetuximab L01XC06 MOAB C225 Ce

chlorambucil L01AA02 CHL, CLB Cl

cisplatin L01XA01 CDDP P

cyclophospham

ide

L01AA01 CTX C

cytarabine L01BC01 ARA-C Cy

dactinomycin L01DA01 DACT Ac

dacarbazine L01AX04 DTIC Dc

daunorubicin L01DB02 DNR Dn

docetaxel L01CD02 TXT Dt

doxorubicin L01DB01 DOX A

epirubicin L01DB03 EPI E

erlotinib L01XX34 OSI 774 Er

estramustine L01XX11 EM Em

etoposide L01CB01 VP-16 Et

fludarabine L01BB05 FAMP Fl

fluoruracil L01BC02 5-FU F

gefitinib L01XX31 ZD 1839 Ge

gemcitabin L01BC05 dFdC G

ifosfamide L01AA06 IFF, IFO If

irinotecan L01XX19 CPT-11 I

melphalan L01AA03 L-PAM Ml

methotrexate L01BA01 MTX M

mitomycin L01DC03 MITO Mi

mitoxantrone L01DB07 DHAD Mx

oxaliplatin L01XA03

1-OHP, L-

OHP

paclitaxel L01CD01 TAX Ta

pemetrexed L01BA04 LY231514 Pe

prednimustine L01AA08 ? Pr

procarbazine L01XB01 PCB Pc

raltitrexed L01BA03 ? Ra

rituximab L01XC02

MOAB IDEC-

C2B8 Ri

temozolomide L01AX03 TMZ Tm

thiotepa L01AC01 TSPA Ts

topotecan L01XX17 TOPO To

trastuzumab L01XC03 MOAB HER2 Tr

vinblastine L01CA01 VBL V

vincristine L01CA02 VCR Vc

vinorelbine L01CA04 VNB Vn

* NCI Drug Dictionary (NCI Drug Dictionary National

Cancer Institute, 2005)

4*[(1;60.0;mg/m2;iv)A+(1;600.0;mg/m2;iv)C&21]+

4*[(1;175.0;mg/m2;iv)Pt&;21]

Figure 6: An example of the identification of the CHR

AC+ paclitaxel

This identification of CHR is stored in a XML

file in the element sysname. The element sysname

acts as a unique identifier, a type of "fingerprint" of

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the CHR and its primary function is to prevent

duplication in the data system.

3 RESULTS

A total of 160 CHR were entered into the database.

The definitions were formed according to the Czech

national guidelines for the cytostatic treatment of

solid tumors (CLS JEP, 2005). The validity of

entries according to International standards was

verified with reference to the International

guidelines NCCN (NCCN, 2006).

3.1 CHR Library Applications

As a demonstration of the use of structured records

of definitions of CHR a publicly accessible web

application was developed with three basic

functions: The Central Library of Chemotherapeutic

Regimens, Dose Intensity (DI) Calculator and

Therapy Organiser.

3.1.1 Search Engine

The Central Library is a simple search engine, that,

according to user entered criteria, searches and

displays the definition of the corresponding regimen.

Registered users have the possibility to add textual

commentaries to each CHR with supplementary

information, while for non registered users all

information is presented in a read only format.

3.1.2 Dose-Intensity Calculator

The DI Calculator enables users to calculate the

dose-intensity for selected CHR according to the

methods in (Hryniuk et al., 1984), and to compare

this with the actual intensities of cytostatics

administered to the patient in question.

3.1.3 Therapy Organizer

The Therapy Organizer enables users to devise time

plans for the administration of chosen CHR. It is

possible to display and print this plan in the form of

a calendar with suggested days and dosages for

individual cytostatics. The functions mentioned are

interconnected, for example, search results from the

Central Library of CHR can be directly used to

create a time plan in Therapy Organizer.

The applications are accessible at the internet

address

http://dios.registry.cz/?sec=software&lang=en

3.2 CHR Derivation

Thanks to a structured CHR library it is possible to

derive standard regimen only from a list of

applicated drugs and dates of administration. This is

useful when dose-intensity is evaluated and

available data doesn’t contain name of standard

regimen. During pilot tests there was success in

correctly deriving 98% of initial CHR from 180

patients who had been administered chemotherapy

for breast carcinoma.

4 CONCLUSIONS

CHR and their administration are routine practice in

contemporary oncology. The development of a

structured, electronic database of standard CHR can

help the faster propagation of information about new

CHR and at the same time enable assessment of their

adherence in clinical practice. The database is

created from XML documents, where every file

represents one CHR.

Unlike other printed or electronic sources about

CHR, this database contains only clear, structured

records of regimes. These records are inserted in

cooperation with expert oncologists. The result is a

new, always up-to-date information source that

forms the base for Dose Intensity Analysis and also

can be used in other computer applications in anti-

tumour therapy area.

ACKNOWLEDGEMENTS

Project DIOS, which addresses problems in anti

tumour chemotherapy, is supported by the grant

2608 from Ministry of Education of the Czech

Republic and by the Amgen Inc.

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