J. M. Klaase

Toxicity and morbidity of isolated limb perfusion

Because a relationship between toxicity and treatment outcome has never been demonstrated for isolated limb perfusion (ILP) with melphalan, it is important to keep the side-effects of the procedure restricted to a minimum. Risk factors for more severe acute regional toxicity have recently been identified with tissue temperature above 40 degrees C and a high melphalan peak concentration being the most important. Acute regional toxicity should be mild taking into account these factors and maintaining the normal physiological conditions in the limb during ILP. This should also decrease the incidence of long-term morbidity, especially ankle stiffness and muscle atrophy, since a relation between the severity of the acute regional tissue reactions and long-term morbidity has been demonstrated. Lymphedema is strongly linked to a concomitant regional lymph node dissection and this operation may be delayed until the acute regional tissue reactions have faded. It is not yet clear whether the addition of tumor necrosis factor-alpha (TNF-alpha) to melphalan increases regional toxicity. In the absence of melphalan leakage to the systemic circulation, systemic toxicity is minimal; this is also true with TNF-alpha. Compared to ILP with melphalan +/- TNF-alpha, ILP with other drugs is less effective and often is associated with increased regional toxicity.

Relation between limb toxicity and treatment outcomes after isolated limb perfusion for recurrent melanoma.

BACKGROUND The optimal toxic reaction of the normal tissues in perfused limbs after isolated limb perfusion (ILP) is unknown. Theoretically, more severe limb toxicity could reflect a concomitant increased toxic effect to the tumor and improved outcomes. We determined whether there is a relation between limb toxicity and treatment outcomes after ILP for recurrent limb melanoma. STUDY DESIGN Among 252 patients with recurrent melanoma of the limbs, treatment outcomes in 192 patients (76%) with no or mild acute limb toxicity were compared with those in 60 (24%) with more severe reactions. Multivariate analysis was used to identify prognostic factors for complete response, limb recurrence-free interval, and survival. RESULTS Among 112 patients with measurable disease, 65 patients (58%) had a complete response and 27 (42%) experienced a relapse in the perfused limb. For complete response, uninvolved regional lymph nodes (p = 0.0025) and ILP using tumor necrosis factor-alpha (p = 0.0076) appeared to be favorable prognostic factors in multivariate analysis. There was no evidence of a relation between limb toxicity and complete response either in univariate (p = 0.16) or multivariate analysis (p = 0.46). For limb recurrent-free interval, only the number of lesions was a significant prognostic factor (p = 0.047); limb toxicity was not (p = 0.095). In 140 patients with recurrent melanoma excised before or at the moment of ILP, independent prognostic factors for survival were gender, the number of positive nodes, and stage of disease. There was no relation between limb toxicity and survival in either univariate (p = 0.53) or multivariate analysis (p = 0.94). Forty-eight (34%) of the 140 patients had a relapse in the perfused limb. No prognostic factors for limb recurrent-free interval could be identified; limb toxicity was not related to relapse time in univariate or multivariate analyses (p = 0.16 and p = 0.14, respectively). CONCLUSIONS More severe acute limb toxicity is not associated with improved outcomes. One should aim at grade II toxicity (slight erythema or edema, compatible with complete recovery) at the most to increase the therapeutic ratio of ILP.

Melphalan tissue concentrations in patients treated with regional isolated perfusion for melanoma of the lower limb

In 14 consecutive patients with recurrent melanoma of the lower limb a total of 35 biopsies were taken at the end of perfusion treatment to assess melphalan tissue concentrations in tumour, skin/subcutis and muscle tissue. In tumour tissue (n = 12) the mean melphalan concentration was 6.8 micrograms g-1, which was significantly higher than that of healthy skin/subcutis (3.2 micrograms g-1; n = 10), but equal to that of muscle tissue (6.5 micrograms g-1; n = 13). The correlation between melphalan concentration in the tissues and the concentration in the perfusate was studied. The latter was assessed in the form of melphalan peak concentration and the area under the curve (AUC0-->60) of the melphalan concentration-time curve. Tumour concentration proved to be correlated linearly with AUC0-->60 (R = 0.6, P = 0.002) and muscle concentration with melphalan peak concentration (R = 0.8, P = 0.04). There was no relation between skin/subcutis concentrations and the perfusate parameters. Further research is warranted to study the relationship between melphalan tissue concentration, tumour response and regional toxicity.

Patient- and treatment-related factors associated with acute regional toxicity after isolated perfusion for melanoma of the extremities

In order to gain some insight into the cause of acute regional toxicity after isolated perfusion using melphalan, 15 patient-related and perfusion-technique-related factors were tested in a logistic regression model. Acute toxicity was graded according to Wieberdinks grading system. In a group of 425 patients, 362 (85%) encountered no or slight toxicity with a grade I or II reaction, and 63 (15%) patients encountered more severe toxicity with a grade III, IV, or V reaction. Most patients were treated with a standard dose of 10 or 13 mg melphalan per liter of perfused tissue for leg and arm perfusions, respectively. Factors associated with a more severe toxicity reaction proved to be tissue temperatures of 40 degrees C or higher, female gender, a deterioration of the gas values of the venous perfusate during perfusion, and perfusion at a proximal level of isolation. Consideration of these prognostic factors may lead to a further decrease of acute regional toxicity in perfusion.

A retrospective comparative study evaluating the results of mild hyperthermic versus controlled normothermic perfusion for recurrent melanoma of the extremities

The aim of this study was to investigate the role of mild hyperthermia (39-40 degrees C) in isolated cytostatic perfusion for patients with recurrent melanoma of the extremities. A total of 218 patients treated with mild hyperthermic perfusion was compared to 166 patients perfused under controlled normothermic conditions (37-38 degrees C). Only patients whose lesions had been excised before or at the moment of perfusion were eligible for this study. A variety of prognostic factors was controlled for in a Cox proportional hazards analysis. The application of mild hyperthermia did not influence limb recurrence-free interval nor survival (corrected P values 0.46 and 0.18, respectively). In this retrospective comparative study, no benefit for mild hyperthermia in regional isolated perfusion could be identified.

A retrospective comparative study evaluating the results of a single-perfusion versus double-perfusion schedule with melphalan in patients with recurrent melanoma of the lower limb

Background. Forty‐two patients with measurable recurrent melanoma of the lower limb were treated according to a double‐perfusion schedule.

Systemic toxicity after isolated limb perfusion with melphalan for melanoma

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-ILP 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 II in five, and grade III in two. Miscellaneous systemic side-effects, including fever and minimal scalp hair loss, occurred in 19 patients (5%). 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 of systemic side-effects. Systemic leakage during ILP was not associated with toxicity, probably due to the low incidence of significant leakage.

Results of a double perfusion schedule with melphalan in patients with melanoma of the lower limb.

From 1985 to 1990 43 patients with measurable locally inoperable or recurrent melanoma of the lower limb were treated according to a double perfusion schedule. The dose of melphalan given in the first perfusion was low (6 mg/l; 1 h; normothermic) in order to make it possible to carry out a second perfusion (9 mg/l; 1 h; normothermic) with a planned short interval of 3-4 weeks. The toxicity after the first perfusion was slight; after the second it was higher with a Wieberdink grade III reaction in 15 patients. A clinical complete remission (CR) was seen in 33 patients (77%) and a partial one in 6 patients. 16 of the 33 patients with a CR recurred in the perfused area after 5 months (range 1-29); the others remained limb recurrence-free (7-44+ months). The overall 3-year survival rate is 50%, 19 patients are alive with no evidence of disease. The double perfusion schedule shows a high CR rate, an acceptable toxicity and is technically feasible.

Value of laboratory tests in monitoring acute regional toxicity after isolated limb perfusion

AbstractBackground: Severe limb toxicity following isolated limb perfusion (ILP) can lead to compartmental compression syndrome and severe rhabdomyolysis, occasionally necessitating amputation of the affected limb. We determined whether laboratory tests for muscle damage and inflammation could predict impending limb toxicity. Methods: All 184 consecutive ILPs performed in our institute from 1988 to 1994 were included in this study. Creatine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (ASAT) and white blood cell (WBC) counts were determined on post-ILP days 1–4, 6, 8, and 15. Results: “Late peak” CK patterns, characterised by a peak on or after the 5th post-perfusion day, were strongly associated with severe limb toxicity (p<0.001). Severe toxicity did develop in 40% of the limbs when CK values exceeded 1000 IU/L on the 2nd to 5th post-ILP day (p<0.001). There was a correlation between the peak CK and the individual grades of toxicity (r=0.6, p<0.001). Serum LDH and ASAT values peaked 2.9 and 3.4 days after the CK peak respectively. Severe limb toxicity was statistically significantly associated with higher WBC counts from the 2nd post-ILP day onwards. Conclusions: CK values exceeding 1000 IU/L after the 1st and WBC counts increasing after the 2nd post-ILP day could be predictors of impending limb toxicity. These patients should be observed closely for signs of compartmental compression syndrome and severe rhabdomyolysis.

Regional Isolated Limb Perfusion in Patients with Malignant Melanoma

In this overview the Amsterdam/Rotterdam ‘controlled’ normothermic (tissue temperatures 37-38 °C) perfusion technique is described. The benefit of the widely used so-called ‘mild’ hyperthermia (39-40°C) is queried. A plea is made to report acute regional toxicity after perfusion according to Wieberdink’s grading system for uniformity. Perfusion has a well-established role in the treatment of locally inoperable melanoma. As an adjunct to surgery, benefit has also been shown in resectable stage II–III recurrent melanoma. For stage I primary melanoma the results of the ongoing EORTC/WHO adjuvant trials are eagerly awaited. In measurable disease an overall response rate of about 80% (with equal proportions of complete and partial remissions) can be obtained by single normothermic or ‘mild’ hyperthermic perfusion. Perfusion strategies that have been investigated to improve the complete response rate are discussed: the application of other cytostatics than melphalan, the role of repeat perfusions, perfusion with melphalan at borderline ‘true’ hyperthermic temperatures (40.5-42°C), sequential perfusion applying ‘true’ hyperthermia (42-43°C) and melphalan separately, and perfusion with the combination of rTNF-alpha, Inter-feron-gamma and melphalan. The ideal of a 100% complete remission rate has been approached in several perfusion strategies but the duration of remission is still rather short. The main issue for the immediate future will therefore be prolongation of the limb recurrence-free interval.