Paediatrics: Chemotherapy

Chemotherapy

May be given as adjuvant treatment (following surgery), or neoadjuvant treatment (before surgery). Combinations of drugs used to increase efficacy, reduce development of resistance, and limit single organ toxicity. Maximizing dose intensity (treatment frequency) increases efficacy.

·  Short-term side-effects: vomiting, myelosuppression, alopecia, and mucositis (inflammation of mucous membranes).

·  Long-term effects: on organ function (kidneys, gonads, hearing, heart) effects variable and, in general, less than effects of radiotherapy.

Antimetabolites Structural analogues of chemicals found in the intermedi-ate steps in the synthesis of nucleic acids and proteins. They include:

·  6-mercaptopurine (6MP): 6-thioguanine (6TG), cytarabine (ara-C), fludarabine (used in leukaemia, NHL).

·  methotrexate (MTX) used in leukaemia, NHL, and OS.

Side-effects include renal toxicity (MTX), myelosuppression, hepatotoxic-ity, and mucositis.

Anti-tumour antibiotics Originally isolated from bacteria and fungi, they have antibiotic and anti-tumour activity. They include the following:

·  Anthracycline: daunorubicin, doxorubicin, idarubicin, mitoxantrone, epirubicin used in leukaemia, NHL, HL, neuroblastoma, Wilms’, sarcoma. Side-effects—myelotoxicity, alopecia, mucositis, cardiotoxicity.

·  Bleomycin used in Hodgkin’s disease, GCTs. Side-effects—include pulmonary toxicity.

·  Actinomycin D (dactinomycin) used in Wilms’ tumour, soft tissue and ES. Side-effects—myelotoxicity (mild), hepatotoxicity.

Epipodophyllotoxins semi-synthetic analogues of podophyllotoxin. They stabilize normally transient DNA–protein complexes by inhibition of topoisomerase I or II:

·  Etoposide (VP16): inhibits topoisomerase II. Used in leukaemia, NHL, neuroblastoma, sarcoma, GCTs, CNS tumours, palliative chemotherapy (low dose). Side-effects—include hypotension, myelotoxicity, alopecia, hepatotoxicity, mucositis, s leukaemia.

·  Topotecan, ironotecan inhibit topoisomerase I. Used in neuroblastoma, sarcoma, and CNS tumours.

Vinca alkaloids Bind to tubulin, interfering with mitotic spindle:

·  Vincristine. Used in leukaemias, NHL, Hodgkin’s disease, CNS tumours, Wilms’, sarcoma. Side-effects include neurotoxicity.

·  Vinblastine. Used in Hodgkin’s disease, anaplastic large cell lymphoma. Side-effects include myelotoxicity and mucositis.

Vinorelbine, new to paediatric practice, causes mild myelosuppression.

Alkylating agents 

Covalent binding to DNA, to prevent replication and transcription:

·Cyclophosphamide, ifosfamide: used in leukaemia, lymphoma, sarcoma, neuroblastoma, high risk Wilms’, CNS tumours.

·Melphalan, busulphan: used in neuroblastoma, ES.

·Chlorambucil (Hodgkin’s disease)

·Lomustine (CCNU): used in CNS tumours.

Side-effects—myelosuppression, alopecia, mucositis, tubular nephropathy (ifos), bladder toxicity (cyclo), encephalopathy (ifos), late effects on fertil-ity, s leukaemia (CCNU).

Platinum compounds

Permanent cross-linking of DNA and inhibition of DNA synthesis. Cisplatin, carboplatin. Used in sarcoma, neuroblastoma, CNS tumours.

Side-effects—high emetogenicity, nephrotoxicity, ototoxicity, neurotox-icity (mainly cisplatin), myelotoxicity (carboplatin).

Other agents

·Dacarbazine (DTIC) methylates nucleophilic sites. Side-effects— mucositis, myelotoxicity, hepatic dysfunction, local pain, ‘flu-like’ symptoms).

·Procarbazine: originally MAOI, but found to be antitumour. Methylates once activated in vitro. Side-effects—myelotoxicity, reduced fertility.

·L-asparaginase: depletes pool of asparagine, needed by some malignancies, e.g. ALL. Side-effects—hypersensitivity, coagulopathy, rarely pancreatitis.

·Amsacrine: complex with DNA and topoisomerase II.

·Hydroxyurea: analogue of urea; inhibits DNA synthesis.

·Steroids: as well as symptom control and reduction of oedema particularly around CNS tumours, have direct anti-tumour effects in haematological malignancies.

Safe administration of chemotherapy

Chemotherapy should only be given by individuals fully trained in the avoidance and management of the complications, working in centres fully equipped and accredited to support chemotherapy.

Route

·Intravenous: central venous access is preferred. Risk of extravasation from peripheral access greatest with vinca alkaloids and anthracyclines.

·IT: usually for treatment or prophylaxis of CNS disease in leukaemia, NHL, and some CNS tumours: safety arrangements for IT` treatment are paramount.

Dosage 

Usually calculated according to surface area. Intravenous fluid to prevent tumour lysis syndrome is required with certain drugs (e.g. ifosfamide, cisplatin, methotrexate). Mesna is given with cyclo-phosphamide and ifosfamide to protect from bladder inflammation.

Monitoring 

The type and level of monitoring depend on agents used. This may include peripheral blood cell counts, GFR measurement, echocardio-gram before and between courses of chemotherapy.