Biomedical subjects
Publications and source records attributed to J Wieberdink.
The first successful cardiac operation in The Netherlands (ligature of a patent ductus arteriosus) was performed in the Central Jewish Hospital at Amsterdam by the Jewish surgeon dr.S.M. Kropveld in August 1941. Due to the German occupation this milestone in the history of Dutch medicine was not published in the usual manner.
From 1975 to 1986, 26 patients with soft tissue tumors of the extremities underwent a total of 29 perfusions. The cytostatics used were doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH) (19 perfusions), melphalan (two perfusions), and a combination of these agents (eight perfusions). Before perfusion most patients had been treated by surgical excision(s), radiotherapy, or systemic chemotherapy. Of 17 patients perfused because of local inoperable tumor, four showed prolonged complete remission of the tumor mass, stable disease was seen in three, and ten showed progression. The complete remissions observed in three patients with aggressive fibromatosis and in one with lymphangiosarcoma occurred after perfusion with doxorubicin combined with melphalan. Doxorubicin added to the perfusate as the sole cytostatic was not effective. Local recurrence was observed in five of nine patients treated by adjuvant perfusion, always after dubiously radical tumor excision. Toxicity was high, especially in the first few years. Tissue necrosis necessitated amputation in three cases (in two after perfusion with doxorubicin and melphalan and in one after repeated perfusion with doxorubicin only). This complication was no longer seen after adjustment of the dosage and dose distribution of doxorubicin, but the morbidity after perfusion with doxorubicin remained considerable.
A series of 57 patients still in follow-up after regional isolated perfusion (RIP) of Stage I-II high-risk melanoma is described. Functional morbidity of the perfused limb was investigated. Median interval after RIP was 5 years. With no regard to recurrent disease subjectively only one patient had severe complaints of the perfused limb. Objective investigation showed no edema or atrophy in 80% of the upper limbs and in 64% of the lower limbs. Concerning the mobility of the joints in the upper limb we found in four cases a disturbed function in several movements. More restriction were observed in the lower leg. Especially the ankle showed severe functional restrictions in more than 25%.
The time course of tissue levels of melphalan during normothermic isolated limb perfusion, and the overall tissue levels per 60 min of perfusion, were estimated from the known pharmacokinetic parameters for a fixed dose of drug per liter of tissue (Benckhuijsen et al., J. Pharmacol Exp Ther 1986; 237: 583-8). The application of differing total doses of drug resulted in varying concentrations in the perfusate plasma. Above a certain plasma level, uptake into the bulk of the tissues did not increase with the area under the plasma concentration vs time curve or its beta-phase. Similar tissue levels were found after perfusion of regions of less than three and a half liter with 13 mg/l as in regions of 5 to 16 liter after perfusion with 10 mg of melphalan per liter. It cannot be predicted from the available data whether the extent of uptake of melphalan into the tumour tissue is equal to or greater than that into the bulk of the tissues. The estimated uptake of drug into the tissues confirms the validity of the dose calculation per liter of tissue. On the basis of the present results, a refined dosimetric formula will be obtainable that includes the desired area under the plasma concentration vs time curve as a determinant for an optimal dose.
The pharmacokinetics of melphalan (L-phenylalanine mustard) in isolated perfusion treatment of patients with melanoma in the limbs have been studied at standardized pseudo-physiological perfusion conditions. Perfused tissue volumes ranged from 2.1 to 16 liters as measured by water displacement. A fixed dose of 10 mg of the drug per liter of perfused tissue was applied. The resulting variation in total melphalan dosage gave rise to varying drug concentrations in the perfusate as the extracorporeal system was operated with a fixed volume of priming fluid. Perfusion with melphalan was applied for 60 min. Concentrations of intact drug were assayed by high-performance liquid chromatography. The melphalan concentrations vs. time for each patient were fitted to a biexponential equation using a nonlinear least-squares computer program. Mean half-lives of 4.7 +/- 0.3 and 53.0 +/- 1.6 min were obtained for the alpha and beta phase, respectively. The hybrid constant alpha remained virtually constant with increasing dose (i.e., increasing drug concentration) and beta also appeared independent of dose levels. With increasing tissue volume plasma clearance was found to diminish per unit of tissue volume. This phenomenon, and a levelling off of the steady-state distribution volume with increasing volume of perfused tissue, are discussed in terms of a possibly restricted transfer of drug from intravascular to the extracellular space and of the possibility of saturation of cellular uptake systems in the bulk of the limb tissues.
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The optimal single dosage of melphalan in isolation perfusion of the limbs for malignant melanoma was assessed. For this purpose a method to determine the volume of the isolated region in the individual patient and a grading system for the reaction of the normal tissues were introduced. A strictly standardized pharmacosurgical routine was developed that permitted an analysis of the correlation between dosage and the grade of toxic reaction in 90 perfusions. The optimal dosage of a cytostatic drug was considered to be the highest amount tolerated at an acceptable risk. Melphalan at 10 mg/l perfused tissue was determined as the likely optimum. This dose provoked remarkably little variation in toxicity, all reactions falling within a safe range. No exception to the applicability of this dosage was encountered.
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