Cytotoxicity therapy

The primary goals of management of tumor lysis syndrome are (1) prevention of renal failure and (2) prevention of electrolyte imbalances. Thus the best treatment for tumor lysis syndrome is prophylaxis to enable delivery of cytotoxic therapy for the underlying malignancy. 

Most often occurs within 12 to 72 hours of initiation of cytotoxic therapy. 

The primary goals of management of tumor lysis syndrome are (1) prevention of renal failure and (2) prevention of electrolyte imbalances. Thus the best treatment for tumor lysis syndrome is prophylaxis to enable delivery of cytotoxic therapy for the underlying malignancy. For patients who present with or develop tumor lysis syndrome despite prophylaxis, treatment goals include (1) decrease uric acid levels, (2) correct electrolyte imbalances, and (3) prevent compromised renal function. These goals should be achieved in a cost-effective manner. 

Prevention of tumor lysis syndrome generally is achieved by increasing the urine output and preventing accumulation of uric acid. Prophylactic strategies should begin immediately on presentation, preferably 48 hours prior to cytotoxic therapy. Treatment modalities primarily increase uric acid solubility, address electrolyte disturbances, and support renal output. 

Allopurinol is the antihyperuricemic drug of choice in patients with a history of urinary stones or impaired renal function, in patients who have lymphoproliferative or myeloproliferative disorders and need pretreatment with a xanthine oxidase inhibitor before initiation of cytotoxic therapy to protect against acute uric acid nephropathy, and in patients with gout who are overproducers of uric acid. 

Neutropenias may also arise as a side effect or deliberate consequence of therapy. For example, some drugs used in the treatment of inflammatory disorders are immunosuppressive, and if these decrease the number of circulating neutrophils to below the critical threshold level, then susceptibility to infection may result. During chemotherapy for the treatment of solid tumours, an inevitable consequence of cytotoxic therapy is that the bone marrow will be destroyed by the drugs thus, patients will have a considerable risk of infection during this induction period. Similarly, during the treatment of haematological disorders (e.g. leukemias and myelodysplastic syndromes), the aim of therapy is to attack the bone marrow so as to destroy... 

Constitutive activation of the P13-K - Akt/PKB survival signaling pathway is a likely mechanism by which many cancers become refractory to cytotoxic therapy. In LNCaP prostate cancer cells, the PTEN is inactivated, leading to constitutive activation of Akt/PKB and resistance to apoptosis. However, apoptosis and inactivation of Akt/PKB can be induced in these cells by treatment with P13-K inhibitors. Surprisingly, androgen, epidermal growth factor, or semm can protect these cells from apoptosis, even in the presence of P13-K inhibitors and without activation of Akt/PKB, indicating the activity of a novel, Akt/PKB-independent survival pathway. This pathway blocks apoptosis at a level prior to caspase 3 activation and release of cytochrome c from mitochondria (Carson et al, 1999)... 

Domperidone is a dopamine antagonist that acts on the chemoreceptor trigger zone. It can therefore be used as an anti-emetic in nausea and vomiting, for example, to counteract side-effects of cytotoxic therapy and to treat nausea associated with dopaminergic drugs used in Parkinson s disease. Unlike hyoscine butlybromide and antihistamines, domperidone is ineffective in motion sickness. 

The absorption of some drugs may be reduced due to damage of the small intestine. This is most likely after cytotoxic therapy. The absorption of phenytoin and verapamil can be reduced by 20-35% in patients taking cytotoxic drugs such as methotrexate, carmustine, or vinblastine for the treatment of malignant disease. The reduced absorption was accompanied by evidence of loss of therapeutic effect. 

The availability of new molecular approaches to the selection of drug therapy is an emerging need, because the traditional approach based on the evaluation of patient and tumor characteristics is clearly far from optimal. Many treated patients do not experience significant benefits from the treatment, while they often experience moderate to severe toxicities. In addition, the development and clinical use of novel molecularly targeted agents (alone or in combination with classical cytotoxic therapy) requires the understanding of the molecular features of the tumors and the identification of tumor markers of response. 

In general, it is preferable to use cytotoxic chemotherapeutic agents in intensive pulse courses every 3-4 weeks rather than to use continuous daily dosage schedules. This allows for maximum effects against neoplastic cell populations with complete hematologic and immunologic recovery between courses rather than leaving the patient continuously suppressed with cytotoxic therapy. This approach reduces adverse effects but does not reduce therapeutic efficacy. 

Gerber, H.P. and N. Ferrara. 2005. Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in pre-clinical studies. Cancer Res. 65 671-680. 

Currently, cetuximab (Erbitux ) is indicated for the treatment of patients with EGFR-expressing metastatic colorectal cancer after failure of irinotecan-including cytotoxic therapy. Depending on the country, cetuximab is approved in combination with irinotecan or in addition as monotherapy. The approved dosing regimen consists of an initial dose of 400 mg/m2 body surface area (BSA), followed by weekly doses of 250 mg/m2. The (intravenous IV) infusion durations are 2 h for the initial infusion, and 1 h for the subsequent weekly infusions. 

Bruns CJ, Koehl GE, Guba M, et al. Rapamycin-induced endothelial cell death and tumor vessel thrombosis potentiate cytotoxic therapy against pancreatic cancer. Clin Cancer Res 2004 10(6) 2109—21 19. 

It is also imperative that nausea and vomiting are minimised as much as possible to ensure that excessive fluid loss does not lead to dehydration. If this were to occur, Mr AC s renal function could deteriorate even further, therefore predisposing him to toxicity from his cytotoxic therapy, especially cisplatin. 

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Panousis, C. Pietersz, G.A. Monoclonal antibody-directed cytotoxic therapy potential in malignant diseases of aging. Drugs Aging. 1999, 1, 1-15. 

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Saeter G, Fossa SD, Norman N. Gynaecomastia following cytotoxic therapy for testicular cancer. Br J Urol 1987 59(4) 348-52. 

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