Assessment of Delivery of Therapeutic Agents in Isolated Limb Perfusion for Malignant Melanoma

Byrne, Dominique Sean (1994) Assessment of Delivery of Therapeutic Agents in Isolated Limb Perfusion for Malignant Melanoma. MD thesis, University of Glasgow.

Abstract

Advanced malignant melanoma is resistant to most forms of treatment. Even primary melanoma is often associated with a very poor prognosis. The incidence of the disease is rapidly increasing in all parts of the world from which data are available, including Scotland. Since its original description in 1957, Isolated Limb Perfusion (ILP) has become an established form of therapy for advanced or recurrent limb melanoma. Its use is associated with high response rates, but these are sometimes short-lived. In Part A, an account of the epidemiology, aetiology and prognosis of malignant melanoma is presented, together with a summary of current standard melanoma treatment (Chapter I). The history of the development of the ILP technique is presented, including a review of published results. The results of ILP in Glasgow are summarised in Chapter II. The technique has been associated with a low morbidity and no mortality. The results observed confirm the very high response rate of recurrent and advanced melanoma to therapeutic ILP. To date, only one small prospective randomized trial of adjuvant ILP for Stage I melanoma of the limbs has been reported. A case-control study of 63 patients treated by adjuvant ILP in Glasgow is presented. This reveals an overall and disease-free survival benefit for ILP patients of 20% and 15% respectively at three years' follow-up. These differences are most apparent for patients with upper limb or poor prognosis (ie. >3.0mm thick) lesions. Despite the fact that ILP has been available since 1957, many aspects of the technique vary from centre to centre so that, even in major reviews, the results quoted may not be consistent and are therefore difficult to compare. In particular, the control of the physiological parameters of extracorporeal circulation and the dosage schedule employed are highly variable. Part B contains a description of clinical and laboratory studies performed by the author aimed at standardising and improving these aspects of ILP. In Chapter III, the author presents a series of clinical studies performed to measure, for the first time, the effect of flow and pressure control on cutaneous perfusion in the isolated limb. These show that currently employed methods do not reliably ensure effective perfusion of skin despite an apparently stable circulation. Consequently, cytotoxic drug delivery to the skin may be suboptimal. The therapeutic outcome of the procedure thus becomes unpredictable. However, the studies reported here show that the extracorporeal perfusion parameters can be regulated by simple, non-invasive monitoring of the transcutaneous oxygen tension (PtcO2) to ensure that the perfusion pressure in the isolated limb is sufficient to support an effective cutaneous circulation. This approach should result in maximal exposure of the tissues of the isolated limb to the cytotoxic drug, although the adapted method does carry the theoretical risk of also increasing the leakage of cytotoxic drug from the isolated circuit to the systemic circulation. The effects of this modification of the perfusion technique have been quantified in a comparative study of melphalan pharmacokinetics, the "quality" of perfusion, uptake of melphalan by the skin, and leakage of melphalan to the systemic circulation in 38 ILPs. This reveals no direct correlation between the quality of perfusion and the concentration of melphalan measured in skin biopsies from individual patients. However, the skin melphalan concentration did correlate with the area under the curve (AUC) of melphalan concentration in the isolated circuit during ILP. Furthermore, this AUC was significantly higher in the group of patients whose ILP was controlled to ensure effective cutaneous perfusion even though there was no significant difference in the dose administered. As a result, the adapted perfusion technique was associated with increased skin melphalan concentrations. There was no evidence of increased leakage of melphalan to the systemic circulation using this technique. In the final section of Chapter 111, the effect of some commonly used vasodilators (which may lower the peripheral resistance in the limb sufficiently to allow effective perfusion at lower pressures ) on the cytotoxicity of melphalan is tested in vitro against human melanoma multicellular tumour spheroids. Although verapamil and hydralazine have in the past been reported to increase the cytotoxicity of several drugs ( including melphalan ) in vitro and in vivo, the experiments reported show no such effect against B0008 melanoma cells in vitro. More importantly, however, neither they nor papaverine were found to exert any adverse effect on melphalan cytotoxicity. In Chapter IV, one of the other major sources of variation in the ILP technique - the choice of dosimetric schedule - is investigated. (Abstract shortened by ProQuest.).

• Item Type: Thesis (MD)
• Qualification Level: Doctoral
• Additional Information: Adviser: Alan McKay
• Keywords: Medicine, Pharmaceutical sciences
• Date of Award: 1994
• Depositing User: Enlighten Team
• Unique ID: glathesis:1994-75662
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 19 Nov 2019 18:59
• Last Modified: 19 Nov 2019 18:59
• URI: https://theses.gla.ac.uk/id/eprint/75662