Paediatric Cancer: Improving Chemotherapeutic Strategies

Pinkerton, C R and Philip, T


Factors affecting the sucess of chemotherapy

Only a minority of paediatric cancers are initially refractory to treatment. CR in ALL and AML ranges from 80-95% and in most solid tumours CR is achieved at the end of chemotherapy, surgery and in some cases, radiotherapy. Disease recurs, however, in around 50% of all solid tumours,

The mechanisms of drug resistance are many and varied. Recently, the role of multi~drug resistance (MDR) has been emphasised. Overexpression of the MDR-1 gene has been demonstrated in soft tissue sarcomas and neuroblastonia. Other mechanisms such as high activity of glutathione transferase, induction of alternative metabolic pathways and alterations in membrane permeability all may be involved. Few of these mechanisms can be manipulated, although there is currently interest in attempting to reverse NIDR using drugs such as verapamil, cyclosporin, and the cyclosporin analogue PSC 833 [611.

In a number of patients an initially chemosensitive tumour recurs because of inadequate initial treatment. This may be a consequence of initial understaging and the administration of an inappropriately low-intensity regimen. Occasionally, inadequate drug doses have been received due to poor patient compliance or a reluctance of physicians to accept the inevitable toxicity of dose escalation.

The number of drugs used, the nature of the drug combination, the treatment intensity and the duration of treatment all depend on the extent of initial disease. Treatment will vary from the simple, nontoxic 10-weekly injections of vineristine for a completely resected WiJms' tumour, to the very intensive, high dose-intensity regimen for inetastatic neuroblastoma with administration of chemotherapy every 10 days, despite neutropenia and thrombocytopenia. The intensifies of the most common chemotherapy regimens are listed in Tables 4 and 5.

Dose-response relationship

The importance of adequate dose has been demonstrated in both leukaemia and solid tumours. Furthermore, there are several retrospective analyses showing a correlation between dose intensity (calculated as dose [fflg/M2 ]/week) and response rates [62,63].

The current randomised European Neuroblastoma Study Group Study V is testing the hypothesis that, by doubling the dose intensity of chemotherapy, both response rate and survival will be improved [641.

A dose-response curve can be constructed for the majority of cytotoxics, in particular the alkylating agents, showing an increased cytotoxic effect with increasing dosage. This relationship is, however, logarithmic and, therefore, dose escalation beyond a certain level is associated with diminishing returns in terms of efficacy.

 

Intensity Disease Regimen
Non-intensive

Rarely myelosuppressive

Wilms' tumour

Localised rhabdomyosarcoma

Hodgkin's lymphoma

Localised NHL

CNS

VA

VA

CHIVPP

CHOP

VCCNU

Moderately intensive

Occasionally myelosuppressive

Malignant teratoma

Wilms' tumour

Osteosarcoma

Rhabdomyosarcoma

Neuroblastoma

JEB

AVAD

ADCDDP

IVA2

OPEC

Intensive*

Usually myelosuppressive

Rhabdomyosarcoma

Ewing's sarcoma

Neuroblastoma

Medulloblastoma

NHL

IVA3

IVAd3

Rapid COJEC

CEV

COPADM

VA=vincristine, actinomycin D; ChIVPP=chlorambucil, vinblastine, procarbazine. prednisolone; CHOP=cyclophosphamide, doxorubicin, vincristine, prednisolone; VCCNU=vincristine, lomustine; JEB=carboplatin (JM-8), etoposide, bleomycin; AVAd=actinomycin D, vincristine, doxorubicin; AdCCDP=doxorubicin, cisplatin; IVA2=ifosfamide (6 g/m'), actinomycin D; OPEC=vincristine, cisplatin, etoposide cyclophosphamide; IVA3=ifosfamide (9 g/m'), actinomyein D; IVAd3=ifosfamide (9 g/m'), doxorubicin; Rapid COJEC=cisplatin, vincristine, carboplatin, etoposide cyclophosphamide given in rapid delivery schedule; CEV=carboplatin, etoposide, vincristine; COPAdM=cyclophosphamide, vincristine, prednisolone, doxorubicin, methotrexate; NHL=non-Hodgkin's lymphoma; CNS=central nervous system.

*Defined as neutrophil count <0.5x109/L and/or platelet count <50x109/L.

 

In vivo evidence supporting the concept of dose response comes from studies in refractory NHL, both in adults and children, where patients resistant to conventional doses of cyclophosphamide have achieved remission when given very high doses of this drug or other alkylating agents. The improved results in AML, high-risk leukaemia and soft tissue sarcomas have all resulted from increases in the doses of conventional agents administered without the use of bone marrow rescue.

 

Disease Standard Investigational
Neuroblastoma * VCR, CDDP, VM-26/VP-16,CP * High-dose CDDP
* + Carboplatin; Megatherapy combinations;
+ mIBG targeting; * Retinoic acid
Medulloblastoma #VCR,CCNU, MTX + CDDP; +Carboplatin, VP-16, Ifos
Wilms' tumour +VCR, Dox, Act Ifos; + VP-16
Hodgkin's disease +Chl, VCR, CP, Pred, Procarbazine VP-16 epirubicin
Non-Hodgkin's lymphoma +VCR, x, CP, Pred, VM-26VP-16, Ara-C + High dose MTX, high dose Ara-C
Rhabdomyosarcoma VCR, Act, CP, Dox # Ifos, high-dose melphalan
Osteosarcoma § High dose MTX, CDDP, Dox § Ifos
Ewing's sarcoma + Ifos, Dox, VCR VP-16 megatherapy combinations
Malignant germ cell tumour + Bleo, VP-16, CDDP. Carboplatin

VCR=vincristine; CDDP=cisplatin; CCNU=Iomustine; VM-26=teniposide; VP-16=etoposide; CP=cyclophosphamide; MTX= methotrexate; Dox=doxorubicin; Act=actinomycin D; Pred=prednisolone; Ifos=ifosfamide; Chl=chlorambucil; Pro=procarbazine; Ara-C=cytosine arabinoside; Bleo=bleomycin. * ENSG regimens (European Neuroblastoma Study Group). + UKCCSG regimens (UK Children's Cancer Study Group). # SIOP regimens (International Society of Paediatric Oncology). § MRC regimens (UK Medical Research Council).

Mega-Therapy (high dose chemotherapy)

With megatherapy, a single agent or a combination of drugs is given over a short period and followed by bone marrow rescue. Drugs suitable for this strategy must be predominantly dose limited by mvelosuppression.

Agents that have, for example, cardiac toxicity, lung toxicity or severe intestinal toxicity cannot be escalated significantly in this manner. Consolidation of remission with high-dose melphalan has been shown to prolong progression-free survival significantly in advanced neuroblastoma, and megatherapy has proved curative in relapsed or refractory NHL.

High-dose chemoradiotherapy, followed by allogeneic BMT has been shown to improve significantly the outcome in first or second remission AML and second remission ALL. It is probably also beneficial for certain subgroups of high-risk ALL in first CR. The efficacy of this strategy owes much, however, to the antitumour effect of the donor transplant with a graft versus leukaemia effect. The inferior results where a syngeneic identical twin donor is used support this conclusion.

The role of megatherapy with autologous bone marrow rescue is less clear. There are claims that this strategy significantly improves outcome in adults with first remission AML and in some children with second CR ALL. At present, randomised, prospective studies are being conducted to prove this, but currently, no firm conclusions can be drawn. In the myeloablative setting, however, autologous peripheral blood progenitor cells (PBPCS) have replaced autologous bone marrow as the primary source of haematopoietic stem cell support.

The role of megatherapy in childhood solid tumours is even more controversial. With the exception of neuroblastoma there is no prospective evaluation demonstrating a therapeutic advantage [651. It is clearly necessary to carry out such studies as the inevitable morbidity due to prolonged myelosuppression, thromboeytopenia, sepsis and other organ toxicity associated with megatherapy must be justified by a significant therapeutic advantage.

Major organ toxicities

(a) Haematological toxicity

With rare exceptions such as asparaginase, vincristine and bleomyein, the majority of effective agents are to some extent myelosuppressive. Most regimens for solid tumours are administered in a pulsed fashion with the nadir of the WBC count and platelet count occurring 10-14 days after a block of treatment. With the moderately intensive and intensive regimens, infection is common, increasingly involving Gram-positive organisms due to the use of central venous catheters. Usually, these are easily treated and rarely cause severe problems or morbidity. The possibility of Gram-negative septicaemia involving organisms such as Pseudomonas, Klebsiella and Escherichia coli requires the routine administration of broad-spectrum antibiotics. There continues to be a significant mortality, ranging from 1-5% with current intensive treatment regimens. Usually, deaths occur in patients who have multi-system failure, in addition to septicaemia. With the ready availability of platelet transfusions, morbidity due to severe haemorrhage or intracranial bleeds is rare, but persistent thrombocytopenia requires prolonged hospitalisation and close monitoring. In the absence of haemorrhage, top-up transfusions for anaemia are required every 2-3 weeks. Myelosuppression and sepsis lead to delays in chemotherapy which may have an adverse effect on efficacy.

One of the most distressing side effects of chemotherapy is severe oral mucositis. This is particularly common in combinations involving the anthracyclines, such as doxorubicin and cisplatin in osteosarcoma and IVAD (ifosfamide, vincristine, doxorubicin) in Ewing's sarcoma. This is usually linked with prolonged neutropenia and may result in oral candidiasis leading to systemic fungal infection. The intensive use of oral decontamination with nystatin and amphotericin B, or more recently oral fluconazole, has reduced the risk of the latter.

(b) Non-haematological toxicity

Small intestinal toxicity with sometimes florid diarrhoea, or persisting weight loss, is an important cause of morbidity. This is more frequently seen with the higher-dose pulsed regimens, such as IVAD or the combinations of cytosine arabinoside and etoposide with anthracyclines, as used in AML.

Less common drug-related toxicities include peripheral neuropathies due to vincristine, seizures associated with high-dose methotrexate, high-dose cytosine arabinoside and high-dose busulphan, and auditory toxicity due to cisplatin.

Hepatotoxicity may result from prolonged methotrexate and 6-mercaptopurine in ALL and may also follow the anthracyclines.

Renal toxicity is most commonly due to prolonged therapy with cisplatin, but the use of the analogue carboplatin should help make this a thing of the past. Unfortunately, the significantly greater myelosuppressive effect of carboplatin may limit its use in combined regimens.

Cardiac toxicity due to high doses of anthracyclines remains a problem, particularly in long-term survivors where there may be significant late morbidity. The new anthracyclines such as epirubicin are less cardiotoxic, but their advantages may be marginal when equally myelotoxic doses are given.


From Pinkerton, C R and Philip, T, (1996) Treatment Strategies in Paediatric Cancer, Consultant Series No. 7, published by GCC Ltd.

 

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