Regional chemotherapy of neoplastic diseases

Abstract

Recent developments have made regional chemotherapy a more rational endeavour. The important pharmacokinetic principles have been defined. The increase in regional exposure achieved is a direct function of a drug's total body clearance and is an inverse function of the permeability-area product (defining ease of egress) for third spaces or of the regional arterial blood flow for intraarterial infusion. Agents having appropriate properties are available. For new agents with appropriate pharmacokinetic parameters, regional chemotherapy may provide a means to examine the dose response against measurable tumors in the regions in question. The observation that most tumors are hypervascular may be crucial to the development of selective treatments using microspheres to deliver therapy in direct proportion to the density of the microvasculature. Regionally infused vasoconstrictors (epinephrine, angiotensin) may allow shunting of flow away from normal tissue toward tumor without potentially serious systemic cardiovascular effects. Investigations and applications of regional chemotherapy have been fostered immensely by the reliably and convenience of the Infusaid implantable pump and by implantable injection ports. The problem of systemic failure with regional approaches still remains but is approachable using pharmacologically rational programs aimed at delivering maximal systemic chemotherapy along with regional treatment. In hepatic arterial therapy, in particular, a randomized prospective study is being considered to examine the impact of such combined treatment versus regional therapy alone and versus systemic chemotherapy alone for metastatic colorectal cancer to liver. Thus, the future for regional chemotherapy appears exciting. There are many opportunities to apply therapeutic principles rationally with the potential of significant benefit to many patients.

Conjugates of Nucleoside Analogs with Lactosaminated Human Albumin to Selectively Increase the Drug Levels in Liver Blood: Requirements for a Regional Chemotherapy

“…In the present study we have conjugated L-HSA with ara-A, FUdR, and dFdC and have shown that the enhancement of drug levels in liver blood can only be achieved by using NAs (ara-A, FUdR), which are rapidly cleared from the bloodstream; this result is in agreement with those of regional chemotherapy performed by a local infusion of drugs (Ensminger and Gyves, 1983). We have also observed that conjugates of rapidly cleared NAs leads to higher drug concentrations locally in liver blood, not only when they are given by bolus injection, but also when they are administered by slow infusion.…”

“…In the regional chemotherapy performed by local infusion, the advantage of drug delivery to the target region depends on the rate of drug elimination from the rest of the body (Ensminger and Gyves, 1983). In the present experiments we studied whether the local drug exposure advantage achieved in liver when NAs are given as galactosyl terminating conjugates is similarly affected by the rate of elimination from bloodstream of the drugs released by liver cells.…”

Postsurgical intra‐incisional 5‐fluorouracil in dogs with incompletely resected, extremity malignant spindle cell tumours: a pilot study

“…Intralesional or intra‐incisional chemotherapy represents an alternative route of drug administration, and it has the advantages of providing extremely high concentrations of the cytostatic drug along all layers of the tumour, thus achieving greater local efficacy, and diminishing systemic adverse events by reducing plasma drug levels 43 . The pharmacologic rationale for regional drug delivery is based on the premise that the rate of drug clearance and exchange from the local compartment is smaller than the total body clearance, accounting for a concentration differential in favour of the tumour 44,45 . Intralesional chemotherapy appears to be a useful strategy to treat cancer; however, there are little data published in the veterinary literature.…”

Using Pharmacologic Data to Plan Clinical Treatments for Patients with Peritoneal Surface Malignancy

“…General statements regarding the effects of vasoactive agents are confusing and sometimes contradictory due to the variety of experimental systems, complex interactions of local-regional and systemic effects of vasopressive agents, and large differences between the neovasculature of tumor nodules and normal capillaries. Both intravenous and intraperitoneal administration of vasoactive molecules in combination with chemotherapeutic drugs has been explored [36, 62, 63]. A preclinical study of the use of an intraperitoneal epinephrine plus intraperitoneal cisplatin in a rat model with PC showed a direct correlation between the intraperitoneal epinephrine concentration and cisplatin accumulation in rat peritoneal tumor nodules [64].…”