The Role of Hyperthermia in Regional Alkylating Agent Chemotherapy

Abstract

The role of hyperthermia during regional alkylating agent chemotherapy is controversial. The aim of this study was to determine the exact contribution of hyperthermia to tumor response during isolated limb infusion with L-phenylalanine mustard. Rats bearing rodent fibrosarcoma on the hindlimb underwent isolated limb infusion with saline, saline plus heat, L-phenylalanine mustard, L-phenylalanine mustard under conditions of normothermia, or L-phenylalanine mustard plus hyperthermia. Heat was administered locally using an in-line hot water circulation loop. Treatment with L-phenylalanine mustard at a concentration of 15 or 50 g/mL was ineffective at producing tumor growth delay (P ‫؍‬ 0.24 and 0.41, respectively). Furthermore, thermal enhancement of L-phenylalanine mustard activity was not seen at 15 g/mL. However, administration of high-dose L-phenylalanine mustard, 50 g/mL, with increasing amounts of heat yielded increasing tumor growth delay, increased regressions, and decreased proliferative index. Although L-phenylalanine mustard infusion under normothermia yielded a tumor growth delay of 7.1 days, combination L-phenylalanine mustard ؉ hyperthermia treatment produced tumor growth delay of 27.0 days (P < 0.01; with two of five animals showing a complete response). Four hours after isolated limb infusion, 50.9% of cells in tumor treated with L-phenylalanine mustard ؉ hyperthermia experienced apoptosis, whereas only 18.1, 16, and 4.4% of cells underwent apoptosis after treatment with L-phenylalanine mustard, saline ؉ hyperthermia, or saline. The mean concentration of L-phenylalanine mustard within tumor relative to perfusate following isolated limb infusion was found to be similar among all groups at 0.023, 0.025, and 0.032 in animals undergoing isolated limb infusion with L-phenylalanine mustard, L-phenylalanine mustard ؉ normothermia, and L-phenylalanine mustard ؉ hyperthermia, respectively. These data indicate a synergistic cytotoxic effect of Lphenylalanine mustard ؉ hyperthermia in isolated limb infusion, which is not attributable to enhanced tumor drug uptake.

Systemic anti-tumour effects of local thermally sensitive liposome therapy

“…In dogs and rats, the half-life of LTSL-DOX is 1 and 2 h, respectively. In humans, however, it is shorter, in the order of 35–40 min [14–16,28,29]. Given the short circulation time of LTSL, it is not likely that enhanced extravasation of the liposomes plays a role in anti-tumour effects at distant sites.…”

Minimally invasive intra-arterial regional therapy for metastatic melanoma: isolated limb infusion and percutaneous hepatic perfusion

“…Hyperthermia, utilized in HILP and to a lesser extent in ILI, may also increase tumor cell uptake of drug and increase drug delivery to the tumor site as suggested by in vitro models [56]. However, thermal enhancement of melphalan cytotoxicity seen in in vivo models has not been readily explained by increased total tumor uptake of drug [57]. One explanation for the discrepancy in findings between in vitro and in vivo studies is that in in vitro systems, tumor cell accumulation of drug is not dependent on blood flow whereas in in vivo systems blood flow is a major determinant of tissue drug delivery.…”

Optimizing Melphalan Pharmacokinetics in Regional Melanoma Therapy: Does Correcting for Ideal Body Weight Alter Regional Response or Toxicity?

“…Hyperthermia has been shown to correlate with increase response rates in ILI, and in ILP. 15–20 Using hypoxia and acidosis are other techniques that are possible with ILI that could be used to improve response rates. Additionally, papaverine is routinely used during ILI at the Sydney Melanoma Unit (SMU) to optimize cutaneous blood flow and increase drug delivery to cutaneous lesions.…”