Isolated limb perfusion with hyperthermia and chemotherapy: predictive factors for regional toxicity (original) (raw)
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Systemic toxicity after isolated limb perfusion with melphalan for melanoma
European Journal of Surgical Oncology (EJSO), 1996
Systemic exposure to melphalan is minimized during isolated limb perfusion (ILP) by isolating a limb from the rest of the body. Consequently, there should be no toxicity to vital organs. At present systemic toxicity after ILP has not been studied in detail. Therefore, the incidence, nature and risk factors of systemic toxicity was retrospectively studied in 368 patients who underwent a single ILP with melphalan between 1978-1990. Some form of systemic toxicity occurred in 98 patients (27%). Nausea and vomiting after the 1st post-lLP day was seen in 73 patients (20%), and in seven (2%) treatment was required. Bone marrow depression was encountered in seven patients (2"/,,): WHO grade ll in five, and grade III in two. Miscellaneous systemic side-effects, including fever and minimal scalp hair loss, occurred in 19 patients (5"/0). Leakage from the isolated circuit to the systemic circulation was measured with radioactive tracers. Mean cumulative leakage during ILP was 0.9%. Systemic toxicity was not increased in patients with leakage greater than 1% or 5%. Female sex was associated with :an increased incidence of systemic toxicity (P<0.05). Age over 60 years (P<0.05) and more severe acute regional toxicity (P<0.05) were correlated with nausea and vomiting. The miscellaneous systemic side-effects were more frequently encountered in women than in men (P<0.05). In conclusion, systemic toxicity was rarely severe, with nausea and vomiting being the most frequently encountered side-effects. Age over 60 years, female sex and more severe acute regional toxic reactions were correlated with an increased incidence ofsystemic side-effects. Systemic leakage during ILP was not associated with toxicity, probably due to the low incidence of significant leakage.
Pharmacokinetics of melphalan in clinical isolation perfusion of the extremities
Cancer research, 1985
The pharmacokinetics of melphalan in clinical hyperthermic isolation perfusion was studied in 16 patients with malignant melanoma. Analysis by computer-generated lines of best fit showed that the loss of melphalan from perfusate conforms best to a biexponential equation. The initial loss with a half-life (t1/2) of approximately 5 to 10 min is interpreted as rapid uptake of melphalan by the tissue of the perfused extremity. The terminal portion of the curve with a half-life of approximately 35 to 50 min is interpreted as due predominantly to the hydrolysis of melphalan, with a lesser component of loss due to absorption of melphalan to the filters and tubing of the perfusion apparatus. Determination of the area under the curve suggests that there is no appreciable uptake of melphalan by the tissue of the perfused extremity after 30 min.
Pharmacokinetics of Melphalan in Clinical Isolation Perfusion of the Extremities1
2000
The pharmacokinetics of melphalan in clinical hyperthermic isolation perfusion was studied in 16 patients with malignant melanoma. Analysis by computer-generated lines of best fit showed that the loss of melphalan from perfusate conforms best to a biexponential equation. The initial loss with a half-life (fi/2) of approximately 5 to 10 min is interpreted as rapid uptake of melphalan by the
British Journal of Cancer, 2001
This study sought to use a microdialysis technique to relate clinical and biochemical responses to the time course of melphalan concentrations in the subcutaneous interstitial space and in tumour tissue (melanoma, malignant fibrous histiocytoma, Merkel cell tumour and osteosarcoma) in patients undergoing regional chemotherapy by Isolated Limb Infusion (ILI). 19 patients undergoing ILI for treatment of various limb malignancies were monitored for intra-operative melphalan concentrations in plasma and, using microdialysis, in subcutaneous and tumour tissues. Peak and mean concentrations of melphalan were significantly higher in plasma than in subcutaneous or tumour microdialysate. There was no significant difference between drug peak and mean concentrations in interstitial and tumour tissue, indicating that there was no preferential uptake of melphalan into the tumours. The time course of melphalan in the microdialysate could be described by a pharmacokinetic model which assumed melphalan distributed from the plasma into the interstitial space. The model also accounted for the vascular dispersion of melphalan in the limb. Tumour response in the whole group to treatment was partial response: 53.8% (n = 7); complete response: 33.3% (n = 5); no response: 6.7% (n = 1). There was a significant association between tumour response and melphalan concentrations measured over time in subcutaneous microdialysate (P < 0.01). No significant relationship existed between the severity of toxic reactions in the limb or peak plasma creatine phosphokinase levels and peak melphalan microdialysate or plasma concentrations. It is concluded that microdialysis is a technique well suited for measuring concentrations of cytotoxic drug during ILI. The possibility of predicting actual concentrations of cytotoxic drug in the limb during ILI using our model opens an opportunity for improved drug dose calculation. The combination of predicting tissue concentrations and monitoring in microdialysate of subcutaneous tissue could help optimise ILI with regard to post-operative limb morbidity and tumour response.
Annals of Surgical Oncology, 2009
Background. Isolated limb infusion (ILI) is a minimally invasive technique delivering regional chemotherapy to treat in-transit extremity melanoma. Determining perioperative factors that could predict toxicity is important to optimize strategies to improve clinical outcomes after regional chemotherapy in melanoma. Methods. Perioperative factors from 171 ILI patients performed at eight centers from 2001 to 2008 were reviewed. The Wieberdink limb toxicity scale and creatine phosphokinase (CK) levels were used to measure toxicity. Logistic regression analysis was used to estimate the association between toxicity and perioperative parameters. Results. Mild (grades I-II) and severe (grades CIII) limb toxicity developed in 68% and 32% of patients, respectively. Melphalan adjusted for ideal body weight (aIBW) and papaverine were used in 47% and 63% of patients, respectively. Median peak CK for all patients was 563 U/l, and median peak occurred at postoperative day 4. On univariate analysis, papaverine and high CK levels ([563 U/l) were significantly associated with higher toxicity. On the contrary, aIBW was significantly associated with a lower risk of severe toxicity. Perfusate blood gas at
BMC Anesthesiology, 2013
Background Hyperthermic isolated limb perfusion (HILP) is used for patients with intractable or extensive in-transit metastatic melanoma of the limb to deliver high concentrations of cytotoxic agents to the affected limb and offers a treatment option in a disease stage with a poor prognosis when no treatment is given. Methods In a retrospective chart review of 17 cases, we studied the anesthetic and hemodynamic changes during HILP and its management. Results HILP was well tolerated except in one case that is described herein. We present summary data of all cases undergoing upper and lower limb perfusion, discuss our current clinical practice of preoperative, perioperative and intraoperative patient care including the management of HILP circuit. Conclusion HILP is a challenging procedure, and requires a team effort including the surgical team, anesthesia care providers, perfusionists and nurses. Intraoperatively, invasive hemodynamic and metabolic monitoring is indispensable to manag...
Hypoxic pelvic and limb perfusion with melphalan and mitomycin C for recurrent limb melanoma
Melanoma Research, 2003
Hypoxic pelvic and limb perfusion by means of a balloon occlusion technique was evaluated in patients with recurrent melanoma of the lower limbs who were nonresponders to isolated hyperthermic limb perfusion or who were not eligible for this procedure. A pilot study was performed in 17 patients, who underwent hypoxic pelvic and limb perfusion with 50 mg/m 2 of melphalan or 50 mg/ m 2 of melphalan and 25 mg/m 2 of mitomycin C. Each procedure was followed by haemofiltration. A leakage monitoring study was performed in five of the 17 patients. The response rate and time to disease progression were the primary endpoints, with overall survival as the secondary endpoint. During the procedures there were no technical, haemodynamic or vascular complications, and no deaths occurred during surgery or in the postoperative period. Significant leakage (median 40%) was measured in the five patients studied. No severe systemic or regional toxicity was observed. After one course of treatment, the objective response rate was 47% (95% confidence interval 22.5-71.5%), the median time to disease progression was 10 months (range 2-40 months), and the 3 year overall survival was 20%. Hypoxic pelvic and limb perfusion seems to be a safe and effective treatment for patients with unresectable recurrent limb melanoma who are not eligible for isolated hyperthermic limb perfusion. Due to the non-homogeneity of the study, with some patients receiving a combination of melphalan and mitomycin C and others receiving only melphalan, it is not possible to make definite conclusions with regard to efficacy. Further studies are necessary to establish whether the response rates can be improved by using different drug regimens. Melanoma
European Journal of Pharmaceutical Sciences
A simple isocratic RP-18 ion-pair high-performance liquid chromatography method with fluorimetric detection and N-phenyl-2,29iminodiethanol as internal standard is presented for the determination of melphalan (the standard cytostatic in isolated limb perfusion (ILP) of patients with malignant melanoma) from aqueous solutions (e.g. cell culture medium or perfusate) and from biological material (melanoma cells, blood, muscle, skin, blood vessel, nerve). In aqueous solutions both hydrolysis products of melphalan were also quantified with high sensitivity, which allowed the measurement of the hydrolysis kinetics in H O, 0.9% NaCl solution and cell culture 2 medium at 37, 41.5 and 438C. Despite its reduced half life at elevated temperatures, melphalan accumulation by SK-MEL-24 cells was significantly higher at 41.58C than at 378C. With optimal solid-phase extraction, 2.6 ng melphalan and 45 ng internal standard were quantified (signal to noise ratio of 10:1) with high precision in less than 50 mg of tissue, collected from a rat after experimental ILP.
Kinetics of melphalan leakage during hyperthermic isolation perfusion in melanoma of the limb
Cancer Chemotherapy and Pharmacology, 1991
The kinetics of melphalan leakage into the peripheral blood were studied in 21 patients undergoing hyperthermic isolation perfusion of the upper or lower limb as an adjuvant treatment in high-risk melanoma; in 5 patients cisplatin was added. The melphalan concentrations in the peripheral blood rose predominantly during the first 20 min of perfusion and levelled out to an apparent steady state of about 0.28 gg/ml in upper extremity perfusions, and 0.34 (without cisplatin) and 0.37 pg/ml (with cisplatin) in lower extremity perfusions. Erythrocytes labelled with technetium Tc 99m, which were added concomitantly with melphalan to the perfusion medium, appeared in the systemic circulation of the patients at an almost constant rate of 0.32% (lower and upper limb perfusions without cisplatin and 0.37% (with cisplatin) of total tracer/min. This perfusate flow rate indicated by labelled erythrocytes completely explained the leakage of melphalan from the perfusion circuit into the peripheral blood. Peak concentrations of melphalan in the peripheral blood were observed immediately after reconstitution of normal hemodynamic conditions once isolation perfusion had been tenninated. This fraction of melphalan might originate from tissue-binding sites, but also from vascular compartments; therefore, a thorough washing-out procedure might minimize this effect.