Cancer in Children: Clinical Management, 5th Edition

Chapter 4. The principles of cancer chemotherapy in children

Gilles Vassal

Arnauld Verschuur

Introduction

The majority of malignancies occurring in childhood are sensitive to cytotoxic chemotherapy. This chemosensitivity is generally attributed to the high proliferation rate of childhood malignancies and the capacity of the malignant cells to become apoptotic. Therefore chemotherapy plays a major role in the treatment of paediatric malignancies and contributes to the still improving outcome for the majority of them. However, several malignancies remain refractory to chemotherapy (some intracranial tumours, several metastatic malignancies, some acute leukaemia, some types of soft tissue sarcoma, advanced stages of neuroblastoma, etc.). Moreover, the long-term toxicity of some chemotherapeutic compounds has become obvious during the last decade. Therefore it is necessary to understand the mechanisms of therapeutic failures and long-term toxicity. The unravelling of these mechanisms may lead to the development of novel treatment modalities.

Principles of chemotherapy

In general, a chemotherapy-based strategy aims first at obtaining complete remission and then at eradicating the minimal residual disease (MRD). Several molecular biologic techniques have been developed for the detection of MRD in solid tumours and haematologic malignancies using a (semi)quantative analysis of tumour-specific and patient-specific gene expression.

In acute lymphoblastic leukaemia (ALL) complete remission is obtained by multi-agent chemotherapy which forms the induction therapy. In addition, intrathecal and intravenous chemotherapy ensures prophylaxis of the central nervous system. According to the protocol and/or patient characteristics, a consolidation or re-induction therapy is applied before the start of maintenance therapy aiming at the eradication of MRD.

In paediatric solid tumours, chemotherapy is adapted to the histologic and/or clinical diagnosis and to the stage of the malignancy. This chemotherapy aims at obtaining regression of the primary tumour in order to facilitate its surgical resection. Moreover, the chemother-apeutic regimen will treat the distant metastases whether they are detectable or not. This preoperative chemotherapy has the advantage of evaluating the chemosensitivity of a particular tumour in a specific patient. It also acts on non-detectable metastases in the earliest stage. Postoperative chemotherapy is essentially required for the treatment of undetectable metastases or MRD. An example of this therapeutic strategy is the treatment of osteosarcoma (see Chapter 19). In other malignancies, surgical removal of the localized primary tumour is followed by chemotherapy, and in some cases radiotherapy, to achieve optimal local control and to treat undetectable distant metastases. An example of this therapeutic strategy is the treatment of medulloblastoma (see Chapter 17).

Chemotherapeutic regimens

Chemotherapy is mostly given in combination regimens of two or more cytotoxic agents. These courses are given sequentially using various combinations to increase the probability of destroying the maximum number of malignant cells. The choice of chemotherapeutic agents depends on several factors such as tumour type, preclinical evidence of in vitro cytotoxicity and cellular mechanisms of cytotoxicity of a specific drug, evidence of in vivo single-drug activity, and the expected toxicity of the proposed chemotherapy course. Sometimes preclinical data from in vitro models or in vivo animal models have shown a synergistic effect of two or more compounds. However, most of the standard chemotherapy regimens developed during the last three decades have not been evaluated in paediatric tumour models before their use in children.

Classification of chemotherapeutic agents

There are several classes of anticancer drugs which are defined by their mode of action. In general, drugs of different classes are chosen for combination regimens in order to use different cytotoxic mechanisms to destroy malignant cells. The following classification is used for drugs prescribed in paediatric oncology:

The antimetabolite compounds interfere with the synthesis of precursors for DNA and RNA. They can be divided into pyrimidine antimetabolites (cytarabine, gemcitabine, cyclopentenyl cytosine, 5-fluorouracil) and purine antimetabolites (6-thioguanine, 6-mercaptopurine, fludarabine, cladribine, clofarabine). All these drugs inhibit the synthesis of DNA and/or RNA.

The antifolates (aminopterin, methotrexate, trimetrexate) form a distinct group of antimetabolites. These drugs inhibit the enzyme dihydrofolate reductase and decrease the synthesis of pyrimidine and purine (deoxy)ribonucleotides, resulting in decreased synthesis of thymidylate (TMP) which is a precursor of DNA.

The antimicrotubule compounds include the vinca alkaloids (vincristine, vinorelbine, vinblastine) and the taxanes (paclitaxel, docetaxel). They interfere with the tubulin assembly required for the formation of microtubules which are essential for the cellular architecture, especially during cell replication when they form the mitotic spindle. Microtubules also have a function in intracellular transport, neurotransmission, and signal transduction pathways.

Alkylating agents include a broad spectrum of cytotoxic drugs. The alkylating drugs are able to form covalent bonds between alkyl groups and cellular molecules such as deoxyribonucleotides in DNA. Alkylation alters DNA and its replication. If these DNA lesions are not repaired, the cell dies. The first alkylating agent to be used clinically was mechlorethamine, also known as nitrogen mustard. This drug was derived from the clinical observations of severe lymphopenia after the use of mustard gas in the First World War. Mechlorethamine is still being used for the treatment of Hodgkin lymphoma. Other alkylating agents that have a prominent role in paediatric oncology are cyclophosphamide, ifosfamide, melphalan, busulfan, thiotepa, and nitrosoureas such as carmustine (BCNU) and lomustine (CCNU). All these agents generate cross-links between or within the two DNA strands. The methylating agents, such as procarbazine, dacarbazine (DTIC), and the recent drug temozolomide, alter DNA but do not generate cross-links. The alkylating agents physically alter DNA. They may induce mutations and secondary malignancies such as myelodysplasia.

Platinum compounds have a similar mode of action to the alkylating agents. However, instead of forming a covalent bond between alkyl groups and nucleotides in DNA, the platinum compound acts through an interaction between the platinum atom and DNA, RNA, or proteins. In DNA, the platinum atom covalently binds to two deoxynucleotides, resulting in intrastrand adducts or interstrand cross-links, leading to DNA damage.

Topoisomerase II inhibitors act by interfering with the enzyme topoisomerase II which plays a role in the unfolding of the DNA molecule during DNA replication, transcription, and repair. The classical examples of topoisomerase II inhibitors are the epipodophyllotoxins such as etoposide (VP16) and teniposide (VM26). The anthracyclins, of which doxorubicin, epirubicin, daunorubicin, and idarubicin are well-known examples, form another major class of topoisomerase II inhibitors. The anthracyclins also act through other cytotoxic mechanisms such as DNA intercalation and the production of reactive oxygen radicals. Mitoxantrone is not a classical anthracyclin and acts predominantly through intercalation of DNA strands.

Topoisomerase I inhibitors include the camptothecins such as topotecan and irinotecan (CPT 11). They act through inhibition of the enzyme topoisomerase I which is involved in DNA relaxation. Topoisomerase I inhibitors have recently been shown to have a beneficial antitumour effect in some paediatric solid tumours.1

Antitumour antibiotics are bleomycin and dactinomycin. The former acts through the oxidative cleavage of DNA, whereas the latter predominantly acts through binding to DNA, inhibition of RNA and protein synthesis, and inhibition of topoisomerases.

L-Asparaginase has a distinct mode of action since it depletes the plasma and intracellular levels of the amino acid asparagine. Since lymphoblasts do not have the capacity to synthethize asparagine because of insufficient activity of the enzyme asparagine synthetase, the drug L-asparaginase has a proven cytotoxic activity in the treatment of ALL.

Some drugs induce differentiation of malignant cells, for example the high doses of retinoic acids used in the treatment of neuroblastoma.

Apoptosis of malignant cells without using the cytotoxic mechanisms summarized above can be achieved by the corticosteroids prednisone, prednisolone, and dexamethasone. They induce apoptosis in ALL cells after binding to the steroid receptors in the cellular membrane. The mechanism through which this leads to apoptosis is being investigated at present

Cytotoxic and targeted drugs developed during the past decade, such as the taxanes (paclitaxel, docetaxel), the topoisomerase I inhibitors (irinotecan, topotecan), temozolomide, and the new platinum compound oxaliplatin, have shown antitumour activity in several adult cancers. These compounds are now in clinical development in paediatric oncology (see Chapter 5). New drugs in clinical development for the haematologic malignancies are the nucleoside analogues fludarabine, cladribine, gemcitabine, cyclopentenyl cytosine, clofarabine, and troxacitabine, and receptor kinase inhibitors such as imatinib.

Toxicity of chemotherapy

Since most chemotherapeutic compounds act on proliferating cells, some normal replicating tissues (bone marrow, gastrointestinal mucosa, and hair follicle bulbs) are at particular risk for toxicity of chemotherapy. Therefore most compounds have a transient toxic effect on these organs. Moreover, some drugs may have a specific toxicity for one or more organs. For example, the anthracyclins are well known for their potential cardiotoxicity. Cisplatinum, and to a lesser extent carboplatin, may be ototoxic and/or nephrotoxic. Methotrexate may be hepatotoxic. In addition, the use of alkylating agents may result in secondary malignancies and impaired fertility in the long term. This latter toxicity depends on the type and cumulative dose of the alkylating agent used and is to a lesser extent dependent on gender. Epipodophyllotoxins may induce secondary myelodysplasia and/or acute myeloblastic leukaemia (AML).

The specific toxicities of the various compounds used in paediatric oncology are listed in Table 4.1. A grading classification for the scoring of toxicity has been developed by the National Cancer Institute [NCI Common Toxicity Criteria (NCI-CTC)] and can be accessed at http://www.ctep.cancer.gov/reporting/ctc.html.

Dose intensity

Since the cytotoxic effects of chemotherapy affect both malignant cells and non-malignant physiologically dividing tissues, the toxicity of each compound and each combination should be taken into account. Because the therapeutic window of a chemotherapeutic compound is narrow and there is often a dose–effect relationship, chemotherapy is frequently given at the maximum tolerated dose to obtain the maximum antitumour effect.2 The concept of dose intensity is defined by the amount of drug administered per unit time. Treatment at high dose intensities has proved to be of benefit in several paediatric tumours, especially Burkitt lymphoma where more than 90 per cent of patients can be cured by intensive combination regimens of relatively short duration (6 months).3 The concept of dose intensity implies a high probability of severe toxicity (either haematologic or non-haematologic) and requires the shortest intervals possible between sequential chemotherapy courses. Any delay in drug administration decreases the intensity of the administered drugs, leading to a possibly less efficacious treatment. During the last decade, novel treatment modalities (anti-emetic therapy, haematopoietic growth factors) have been developed for supportive care (see Chapter 8) to reduce the toxic side effects of chemotherapy while maintaining its dose intensity.

High-dose chemotherapy

Another step forward for dose intensity is high-dose chemotherapy followed by autologous or allogeneic haematopoietic stem cell transplantation. Several cytotoxic compounds have a linear or almost linear dose–effect relationship. These compounds are suitable for high-dose administration, especially when the toxicity of these drugs is essentially haematologic since the reinfusion of haematopoietic stem cells will ensure effective reconstitution of haematopoiesis after the chemotherapy. Thus the maximum therapeutic effect is obtained and non-haematologic toxicity becomes dose limiting. High-dose chemotherapy strategies are generally applied in situations of very good partial or complete remission in patients with a chemosensitive tumour but a high risk of relapse. The dose–effect relationship increases the probability of destroying residual malignant cells and/or overcoming cellular mechanisms of drug resistance. The most prominent examples of chemotherapeutic agents used for high-dose chemotherapy are the alkylating compounds such as cyclophosphamide, busulfan, melphalan, and thiotepa. In paediatric oncology, high-dose chemotherapy is used in neuroblastoma, Ewing sarcoma, osteosarcoma, medulloblastoma, and relapsed or high-risk leukaemia.4,5 The quality of haematopoietic stem cell grafts has increased in the last few years, such that such a strategy can sometimes be performed in an ambulatory setting. However, the real value of high-dose treatment strategies in paediatric oncology is still a matter of research and debate.

In the case of allogeneic grafts, especially in acute leukaemia, the immunologic phenomenon of graft versus leukaemia has an additional antitumour effect in addition to the cytotoxic effects of chemotherapy and total body irradiation.

Table 4.1. Specific adverse effects of cytotoxic compounds used in paediatric oncology*

Compound

Short-term side effects

Long-term side effects

Asparaginase

Clotting disorders, anaphylactic reactions, pancreatitis, hyperglycaemia

Unknown

Bleomycin

Fever, malaise, skin rash

Pulmonary fibrosis

Busulfan

Veno-occlusive disease, seizures, hyperpigmentation

Hyperpigmentation, pulmonary fibrosis, fertility disorders

Carboplatin

Ototoxicity, allergic reactions

Ototoxicity

Cisplatin

Renal toxicity, ototoxicity, radiosensitizing

Renal toxicity, ototoxicity

Cyclophosphamide

Haemorrhagic cystitis

Fertility disorders, secondary leukaemia

Cytarabine

Mucositis, rash, conjunctitis, fever, encephalopathy, seizures, pancreatitis

Encephalopathy

Dactinomycin

Jaundice, veno-occlusive disease, radiosensitizing

Unknown

Daunorubicin

Mucositis, cardiomyopathy, radiosensitizing

Cardiomyopathy, secondary leukaemia

Dexamethasone

Mood disorders, increased appetite, Cushingoid appearance, muscular atrophy, bone demineralization, skin disorders

Bone fractures, avascular femoral head necrosis, vertebral flattening, hypocortisolism

Doxorubicin

Mucositis, cardiomyopathy, radiosensitizing

Cardiomyopathy, secondary leukaemia

Epirubicin

Mucositis, cardiomyopathy, radiosensitizing

Cardiomyopathy, secondary leukaemia

Etoposide (VP 16)

Allergic reactions, mucositis

Secondary leukaemia

Fludarabine

Mucositis, fever, pneumonitis, neurotoxicity, hepatitis

Unknown

Idarubicin

Mucositis, cardiomyopathy, radiosensitizing

Cardiomyopathy, secondary leukaemias

Ifosfamide

Haemorrhagic cystitis, tubulopathy, encephalopathy, seizures

Tubular and glomerular toxicity, fertility disorders

Irinotecan

Abdominal pain, diarrhoea, sweating, hyperlacrimation, salivary excess

Unknown

Melphalan

Mucositis, interstitial pneumonitis

Pulmonary fibrosis, fertility disorders

6-Mercaptopurine

Hepatitis

Unknown

Methotrexate

Hepatitis, mucositis, encephalopathy, renal toxicity

Liver fibrosis, encephalopathy

Mitoxantrone

Mucositis, cardiomyopathy

Cardiomyopathy

Prednisolone

Mood disorders, increased appetite, Cushingoid appearance, muscular atrophy, bone demineralization, skin disorders

Bone fractures, avascular femoral head necrosis, vertebral flattening, hypocortisolism

Procarbazine

Allergic reactions, hepatic dysfunction, headache, paraesthesia, hallucinations

Fertility disorders

Teniposide (VM 26)

Allergic reactions, mucositis

Secondary leukaemia

6-Thioguanine

Hepatitis

 

Thiotepa

Headache, encephalopathy, dizziness, allergic reactions, skin rash, fever

Fertility disorders

Topotecan

Mucositis, radiosensitizing

Unknown

Vinblastine

Paraesthesia, neuralgia, sensory disorders, hypertension, Raynaud's phenomenon

Raynaud's phenomenon

Vincristine

Paraesthesia, neuralgia, muscular weakness, sensory disorders, constipation, ileus, abdominal cramps, seizures, SIADH

Neurotoxicity

* The adverse effects are categorized as short-term (days to weeks) and long-term (months to years) side effects. General adverse effects such as bone marrow depression, gastrointestinal toxicity, and alopecia are not included since these side effects are considered as common to all chemotherapy.

 

Response evaluation

The evaluation of tumour response to treatment is based upon strict criteria of measurements in one, two, or three dimensions of all measurable tumour sites. There is international consensus for documenting response according to WHO or RECIST criteria (Table 4.2). In some tumour types specific response evaluation criteria can be used, as is the case for neuroblastoma where the International Neuroblastoma Response Criteria are generally adopted.

Drug resistance

During the past three decades there has been much preclinical research aimed at unravelling the various mechanisms of drug resistance. Multidrug resistance (MDR) is a well-known mechanism of drug resistance. Several proteins are implicated including MDR1, multidrug resistance proteins 1–8 (MRP), breast cancer resistance protein (BCRP), and lung-resistance-related protein (LRP). High expression of these membrane proteins in tumour cells has been correlated with a poor outcome in some malignancies in paediatric oncology, although the issue remains controversial. Various preclinical models have been developed to circumvent the MDR-related mechanism of drug resistance. However, clinical trials using MDR blocking agents (verapamil, cyclosporin A, PSC 833) have failed to demonstrate a clinical benefit. Apparently, other cellular mechanisms that are not circumvented by MDR blocking agents also contribute to drug resistance.

Table 4.2. Methods of response evaluation after chemotherapy

 

WHO*

RECIST†

Measurements

Product of two perpendicular diameters; sum of products, in case of multiple lesions

Largest diameter; sum of diameters, in case of multiple lesions

Complete response (CR)

Total regression of any lesion

Total regression of any lesion

Partial response (PR)

≥50% decrease and absence of any new lesion

≥30% decrease and absence of any new lesion

Stable disease (SD)

<50% decrease or <25% increase

<30% decrease or <20% increase

Progressive disease (PD)

≥25% increase or presence of new lesion(s)

≥20% increase or presence of new lesion(s)

Objective response rate

CR + PR

CR + PR

*World Health Organization (1979). Handbook for Reporting Results of Cancer Treatment. Geneva: WHO, 48.
†Therasse P, Arbuck SG, Eisenhauer EA, et al. (2000). New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92, 205–16.

Dosing drugs in paediatric oncology

Body surface area

The principle of using body surface area (BSA) for dosing chemotherapeutic compounds in oncology results from pharmacologic research between species and between adults and children. These research data showed that the most reliable method of comparing physiologic variables, such as glomerular filtration rate, cardiac output and basal metabolic rate, between species is by correcting for BSA.6 Using body weight instead of BSA proved to result in an unreliable interspecies correction of all mechanisms contributing to the clearance and metabolism of drugs. Since the therapeutic window of cytotoxic compounds is generally narrow and cytotoxic drugs are generally prescribed at nearly the maximum tolerated dose, it is common practice in paediatric oncology to prescribe drugs in milligrams per square meter to correct for morphometric variability between patients. Although the use of BSA is controversial in adult oncology, the variation of weight and length is so great in children that the prescription should still be based on BSA in paediatric oncology. Moreover, if cytotoxic drugs are prescribed per square meter, it is easier to determine a starting dose for phase I clinical trials in humans based on the data reported in toxicologic studies in animal models.

The BSA can be calculated using either formulae or nomograms. The gold standard formula was proposed in 1916 by Dubois and Dubois7 (Table 4.3). Although this formula is very reliable, it is not easy to use. Many other formulae,8 taking into account either weight and length or weight only, have been validated (Table 4.3).

Chemotherapy in infants

The tolerance to chemotherapy at a given dose is poorer in infants than in older children.9 Therefore doses should be reduced in infants. Several physiologic mechanisms that contribute to the pharmacokinetics of drugs mature during the first year of life.10 For instance, the water content of the human body decreases from 75 per cent at birth to 60 per cent at 1 year and 55 per cent in the adult. The content of plasma proteins also changes during the first year of life. Hepatic drug metabolizing enzymes (cytochrome P-450 isoenzymes, UDP glucuronyltransferase, glutathione metabolizing enzymes) acquire their physiologic activity between 6 and 12 months of age. The renal glomerular filtration rate attains values comparable to the adult at the age of 5 months. All these developing clearance mechanisms contribute to a poor tolerance of infants to chemotherapy.

Table 4.3. Formulae for calculating body surface area (BSA), body mass index (BMI), and ideal body weight

Dubois' formula

BSA(m2)= W0.425 × L0.725 × 0.007184

Mosteller's formula

BSA(m2W × L/3600

Formula without using length

BSA(m2) (4W + 7)/(W + 90)

Body mass index (Quetelet index)

BMI (kg/m2) = [W(kg)]/[L(m)]2

Lawrence's formula

Ideal body weight (kg) [length (cm) 100] {[length (cm) 150]/K}

W, body weight (kg; L, body length (cm); K = 4 for males and K = µ 2 for females.

Table 4.4. Comparison between dose prescribed in mg/m2 and dose prescribed in mg/kg for children

Age

Weight (kg)

BSA (m2)

Calculated dose (mg)

Dose reduction (%)

For 100 mg/m2

For 3.33 mg/kg

10 years

30

1

100

100

0

1 year

10

0.46

46

33

28

3 months

6

0.29

29

20

31

Generally, chemotherapy in infants should be prescribed based on milligrams per kilogram body weight rather than milligrams per square meter since the relationship between body weight and BSA in infants is different from that in older children (Table 4.4 and Fig. 4.1). A dose prescribed in milligrams per square meter in infants leads to a higher dose than a prescription in milligrams per kilogram (Table 4.4). One should be even more cautious when prescribing cytotoxic drugs for very young children (<3 months).

Chemotherapy in obese patients

Obesity is associated with modifications in body composition which may change the pharmacokinetics of the cytotoxic compounds and result in inadequate dosing and increased toxicity.11 The increased content of fatty tissues will alter the distribution volume of drugs depending on the affinity of the drug for fatty tissues and plasma proteins. Fatty degeneration of liver tissue may also modify the hepatic metabolizing capacities in obese patients. The diagnosis of obesity is defined by an increased body mass index (BMI) according to the Quetelet index (Table 4.3).

Fig. 4.1 Development of ratio of body weight (BW) to body surface area (BSA) during childhood.

Upper reference values for adults (>18 years) are 23 kg/m2 in males and 21 kg/m2 in females. Overweight and obesity are defined by BMI values > 25 kg/m2 and > 30 kg/m2, respectively. In children the BMI changes with increasing age. Therefore the upper reference values of BMI defining obesity depend on age and sex (Table 4.5).12

In order to prescribe cytotoxic drugs appropriately in obese patients it would be necessary to have pharmacokinetic data for a drug in a population of obese patients compared with patients with a normal body composition. However, no such data are available for most cytotoxic compounds. In the absence of such pharmacokinetic data, it is recommended that a cytotoxic compound is prescribed on the basis of the ideal body weight rather than the real body weight. The ideal body weight for adolescents and young adults can be calculated using Lawrence's formula (Table 4.3). In younger children the ideal body weight is determined by the body weight corresponding to the actual length of the patient.12

Prescribing chemotherapy in extreme situations

Some patients may require chemotherapy in an acute situation where mechanisms of clearance are failing either because of the malignancy or as a result of previous treatments. For example, there might be renal or hepatic insufficiency resulting in prolonged clearance of a drug and therefore potentially increased toxicity. In such situations, prescribing chemotherapy should be adapted to the patient, taking into account the type of drug used and the mechanisms of clearance that are relevant for that drug. Moreover, the potentially specific toxicity for the affected organ should be taken into account when prescribing a cytotoxic drug. In these extreme situations it might be useful to determine plasma concentrations of the prescribed drugs using a low test dose. Computer models can predict an adjusted dose if clearance is decreased.

For recommendations or dose adaptations in cases of renal or hepatic insufficiency the reader is referred to the handbook Cancer Chemotherapy and Biotherapy13

Intrathecal chemotherapy

The volume of the central nervous system is proportionally larger in the young child than in the adolescent and adult and does not correlate with the BSA. A child aged 4–6 years has a central nervous system volume of 80–90 per cent of the adult brain, whereas the adult value of the BSA is not attained until the age of 16–18 years.14 Thus intrathecal therapy, such as metrotrexate, should be prescribed in an absolute dose (milligrams) depending on the age rather than in milligrams per square meter.

Pharmacogenetics and drug interactions

The metabolic mechanisms of an organism contribute to the clearance of drugs by transforming them to metabolites which facilitate renal or biliary excretion. These metabolites usually have less therapeutic activity than the parent drug, or no therapeutic activity at all, although some may still have a strong cytotoxic effect. Many enzymes are implicated in the biotrans-formation of drugs; the cytochrome P-450 isoenzymes, the glucuronidation pathways, and detoxifying enzymes implicated in glutathione metabolism are the most relevant. The various enzyme activities influence the plasma concentration of the drugs and thus the concentrations in tumour tissue. It is useful to know the metabolic pathways of drugs in order to identify or prevent drug interactions. Hepatic mechanisms such as CYP450 enzyme induction or enzyme inhibition may alter the effect of a cytotoxic drug dramatically. Phenobarbital, carbamazepine, and phenytoin may induce activity of the CYP3A4 and CYP2C9 isoenzymes, and thus may increase the biotransformation and clearance of many cytotoxic drugs.15 Drugs such as fluconazole, itraconazole and valproic acid may inhibit the activity of a number of CYP isoenzymes, resulting in higher plasma concentrations and potentially more toxicity of cytotoxic drugs metabolized by these isoenzymes. Therefore drug interactions should be taken into account when prescribing chemotherapy and non-cytotoxic drugs.

Table 4.5. International cut-off points for body mass index for overweight and obesity by sex for ages 2–18 years12

Age (years)

Overweight

Obesity

Males

Females

Males

Females

2

18.41

18.02

20.09

19.81

2.5

18.13

17.76

19.8

19.55

3

17.89

17.56

19.57

19.36

3.5

17.69

17.4

19.39

19.23

4

17.55

17.28

19.29

19.15

4.5

17.47

17.19

19.26

19.12

5

17.42

17.15

19.3

19.17

5.5

17.45

17.2

19.47

19.34

6

17.55

17.34

19.78

19.65

6.5

17.71

17.53

20.23

20.08

7

17.92

17.75

20.63

20.51

7.5

18.16

18.03

21.09

21.01

8

18.44

18.35

21.6

21.57

8.5

18.76

18.69

22.17

22.18

9

19.1

19.07

22.77

22.81

9.5

19.46

19.45

23.39

23.46

10

19.84

19.86

24

24.11

10.5

20.2

20.29

24.57

24.77

11

20.55

20.74

25.1

25.42

11.5

20.89

21.2

25.58

26.05

12

21.22

21.68

26.02

26.67

12.5

21.56

22.14

26.43

27.24

13

21.91

22.58

26.84

27.76

13.5

22.27

22.98

27.25

28.2

14

22.62

23.34

27.63

28.57

14.5

22.96

23.66

27.98

28.87

15

23.29

23.94

28.3

29.11

15.5

23.6

24.17

28.6

29.29

16

23.9

24.37

28.88

29.43

16.5

24.19

24.54

29.14

29.56

17

24.46

24.7

29.41

29.69

17.5

24.73

24.85

29.7

29.84

18

25

25

30

30

During the past decade the influences of these pharmacokinetic-modifying enzymes have been revealed and this has led to population-based studies of pharmacogenetics.16 Genetic polymorphisms of these enzymes may lead to variable phenotypes, resulting in different enzyme activities from patient to patient and thus a modified clearance. An example of such pharmacogenetic variability is encountered in the metabolism of 6-mercaptopurine which is inactivated by the enzyme thiopurine methyltranferase (TPMT).17

In this era of insight into the human genome, new genetic polymorphisms of enzymes or receptors will be detected that are implicated in the metabolism of cytotoxic and non-cytotoxic agents. This may lead to patient-adapted prescription of cytotoxic drugs in the future, taking into account the individual genotype and phenotype of clearance mechanisms.

References

1. Vassal G, Doz F, Frappaz D, et al. (2003). A phase I study of irinotecan as a 3-week schedule in children with refractory recurrent solid tumours. J Clin Oncol 21, 3844–52.

2. Frei E III, Elias A, Wheeler C, Richardson P, Hryniuk W (1998). The relationship between high-dose treatment and combination chemotherapy: the concept of summation dose intensity. Clin Cancer Res 4, 2027–37.

3. Patte C, Auperin A, Michon J, et al. (2001). The Société Franc¸aise d'Oncologie Pediatrique LMB89 protocol: highly effective multiagent chemotherapy tailored to the tumor burden and initial response in 561 unselected children with B-cell lymphomas and L3 leukemia. Blood 97, 3370–9.

4. Hartmann O (1995). New strategies for the application of high-dose chemotherapy with haematopoietic support in paediatric solid tumours. Ann Oncol 6 (Suppl 4), 13–16.

5. Vassal G, Tranchand B, Valteau-Couanet D, et al. (2001).Pharmacodynamics of tandem high-dose melphalan with peripheral blood stem cell transplantation in children with neuroblastoma and medulloblastoma. Bone Marrow Transplant 27, 471–7.

6. Reilly JJ, Workman P (1993). 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 32, 411–18.

7. Dubois D and Dubois EF (1916). A formula to estimate the approximate surface area if height and weight be known. Arch Int Med 17, 863–71.

8. Mosteller RD (1987). Simplified calculation of body-surface area. N Engl J Med 317, 1098.

9. Jones B, Breslow NE, Takashima J (1984). Toxic deaths in the Second National Wilms' Tumor Study. J Clin Oncol 2, 1028–33.

10. McLeod HL, Relling MV, Crom WR, et al. (1992). Disposition of antineoplastic agents in the very young child. Br J Cancer 18 (Suppl), S23–9.

11. Cheymol G (2000). Effects of obesity on pharmacokinetics: implications for drug therapy. Clin Pharmacokinet 39, 215–31.

12. Cole TJ, Bellizzi MC, Flegal KM, Dietz WH (2000). Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ 320, 1240–3.

13. Chabner BA, Longo DL (2001). Cancer Chemotherapy and Biotherapy. Principles and Practice. Philadelphia, PA: Lippincott–Williams & Wilkins.

14. Bleyer WA, Dedrick RL (1977). Clinical pharmacology of intrathecal methotrexate. I. Pharmacokinetics in nontoxic patients after lumbar injection. Cancer Treat Rep 61, 703–8.

15. Vecht CJ, Wagner GL, Wilms EB (2003). Interactions between antiepileptic and chemotherapeutic drugs. Lancet Neurol 2, 404–9.

16. Boddy AV, Ratain MJ (1997). Pharmacogenetics in cancer etiology and chemotherapy. Clin Cancer Res 3, 1025–30.

17. McLeod HL, Krynetski EY, Relling MV, Evans WE (2000). Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. Leukemia 14, 567–72.



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