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Hypothesis: In patients with truly unresectable melanoma of the extremities, results after isolated limb perfusion (ILP) are absent in the literature. Complete response rates are probably lower than the reported 54% for locoregional recurrent melanoma. In these patients, ILP with melphalan and tumor necrosis factor alpha (TNF-alpha) could be superior to ILP with melphalan alone., Design: Retrospective analysis with a median follow-up period of 21 months (interquartile range, 9-40 months)., Setting: Two tertiary care cancer centers in the Netherlands., Patients: We assessed all 130 consecutive patients who underwent ILP for unresectable melanoma of the extremities, performed between 1978 and 2001. Of these patients, 38% had stage IIIA melanoma and 45% had stage IIIAB melanoma according to criteria of the MD Anderson Cancer Center. Lesions were considered unresectable on the basis of their size, number, or localization., Interventions: Forty ILPs were performed with melphalan, and 90 were done with TNF-alpha and melphalan., Main Outcome Measures: Response rate, disease-free survival, limb salvage rate, and overall survival., Results: In 45% of the patients, a complete response was attained after ILP with melphalan (95% confidence interval, 29%-61%) compared with 59% after ILP with TNF-alpha and melphalan (95% confidence interval, 49%-69%; P = .14). The time to complete response was 3 months (interquartile range, 2-6 months) vs 2 months (interquartile range, 1-3 months; P = .01), respectively. The recurrence rate and median limb recurrence-free survival were not significantly different for both ILP types. The overall limb salvage rate was 96%. Overall 5-year survival was 29% (95% confidence interval, 20%-38%). The ILP type was not an independent prognostic factor for complete response, nor was limb recurrence-free survival, whereas stage IIIA was a favorable prognostic factor (P = .01 and P = .02, respectively). Favorable prognostic factors for improved survival were complete response (P<.001) and a tumor size of 3 cm or less (P = .01)., Conclusions: In more than half of the patients with truly unresectable melanoma of the extremities, a complete response was obtained after ILP with melphalan with or without TNF-alpha. The ILP type was not an independent prognostic factor for complete response, limb recurrence-free survival, or overall survival.

Background: The influence of isolated limb perfusion (ILP) on the limb recurrence-free interval (LRFI) and the number of lesions per recurrence was studied for patients with frequently recurring regional in-transit metastases previously managed by excisional surgery., Methods: All 43 patients who had their first ILP for a third or further limb recurrence were selected from our computer database of 451 patients who underwent therapeutic ILP for recurrent extremity melanoma in our centers. Eighteen patients had resectable and 25 had locally unresectable lesions at the time of ILP. The patients had a total of 269 intervals between treatment of their primary melanoma and last recurrence or last follow-up. Median follow-up was 35 months (interquartile range, 14-64 months)., Results: The median LRFI decreases over time from primary melanoma to the third or further recurrence for which ILP was performed (P < 0.001). The median LRFI is 4.7 times longer (95% confidence interval [CI], 2.8-7.9; P < 0.001) after ILP in comparison with the last interval before ILP. Patients with resectable lesions have a median LRFI that is 5.9 times longer (95% CI, 2.7-13; P < 0.001). In all patients, the number of lesions increases by 22% per recurrence number (95% CI, 10%-35%; P = 0.02). At the same recurrence number, patients before ILP have a 2.6-fold higher (95% CI, 1.6-4.5) mean number of lesions than do patients after ILP (P < 0.001)., Conclusions: ILP lengthens the LRFI and decreases the number of lesions per recurrence significantly in patients with repeatedly recurrent limb melanoma. Therefore, ILP could be a valuable adjunct to excisional surgery for in-transit metastases in these patients whose LRFIs tend to shorten over time.

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.

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.

Background: Melanoma recurring locoregionally after isolated limb perfusion (ILP) constitutes a therapeutic dilemma. Major amputation is a deterrent option for local control and palliation in these patients who have a rather poor prognosis. Little is known about the feasibility and efficacy of repeat ILP in these situations., Study Design: From 1978 to 1993, 28 patients with recurrent melanoma after ILP were retreated with various ILP procedures using melphalan. Eighteen patients underwent reperfusion by a single and four by a multiple normothermic schedule. Hyperthermia was applied in six repeat ILP procedures., Results: A complete remission was achieved in 14 (74 percent) of 19 patients with measurable disease, with a median limb recurrence-free interval of 11 months. A partial remission was obtained in one patient (5 percent). Two patients had no change of disease and two patients had progressive disease. In the remaining nine patients, all macroscopic tumor tissue was excised before or during the repeat ILP procedure. The median limb recurrence-free interval of these nine patients was 15 months. After a median follow-up period of 30 months after repeat ILP, seven (25 percent) of the 28 total patients were alive without disease. Acute regional tissue toxicity was more severe after repeat ILP than after the first procedure (p < 0.05). Long-term regional morbidity occurred in 11 percent of the patients., Conclusions: A high complete remission rate can be obtained with repeat ILP using melphalan. However, the high limb recurrence rate and relatively short limb recurrence-free interval need improvement. Increased acute regional toxicity after repeat ILP can be explained by the use of more intensive schedules.

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 Wieberdink's 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.

From 1978 to 1990, 24 patients with subungual melanoma (MD Anderson Stage I, 17, Stage III, 7 patients) were treated with amputation of a digit and regional isolated perfusion with melphalan. The lesions were located on the big toe in 14 (58%) patients. Median delay in definitive treatment was 21 months, while 14 patients (58%) had been subjected to some form of inadequate treatment before correct diagnosis was made. Median follow-up for the living patients was 48 months. Overall 5-year survival was 54% (Stage I, 68%, Stage III, 19% (log-rank P = 0.003)). Sex and site of the lesion did not influence survival. Compared to literature data of patients treated by amputation alone, no improvement in survival could be demonstrated despite perfusion treatment. Moreover, two limb and 7 regional node recurrences were seen. The benefit of adjuvant perfusion in the treatment of Stage I subungual melanoma has not been demonstrated in this study. The results of prospective randomized trials in primary high-risk extremity melanoma have to be awaited.

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.

Hyperthermic perfusion was given as a palliative treatment in three patients with a bulky tumour in the leg. During the treatment, temperature and pH data were collected in both tumour and normal tissues. The hyperthermia dose administered was 2 h at 41.9-42.7 degrees C. It was found that the temperature distribution was far from homogeneous. In one case tumour pH could be monitored throughout the whole treatment procedure. The tumour pH showed a steep decrease during the initial phase of the perfusion, from a mean value of 7.11 to 5.94 at the start of the hyperthermic phase. Subcutis pH decreased only 0.29 units during the whole procedure. In all three patients considerable tumour regression was observed, without severe toxicity. Hyperthermic perfusion appeared to be an effective debulking treatment. The pH decrease in tumour tissue, immediately before hyperthermia, may be responsible for the remarkable effectiveness of the hyperthermic treatment.