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10.1245/ASO.2005.03.060
Annals of Surgical Oncology 12:609-615 (2005)
© 2005 Society of Surgical Oncology
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Original Article

Efficacy of Repeat Isolated Limb Perfusions With Tumor Necrosis Factor {alpha} and Melphalan for Multiple In-Transit Metastases in Patients with Prior Isolated Limb Perfusion Failure

Dirk J. Grünhagen, MD1, Boudewijn van Etten, MD1, Flavia Brunstein, MD1, Wilfried J. Graveland, MSc2, Albertus N. van Geel, MD, PhD1, Johannes H. W. de Wilt, MD, PhD1 and Alexander M. M. Eggermont, MD, PhD1

1 Department of Surgical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, PO Box 5201, 3008 AE, Rotterdam, The Netherlands
2 Department of Statistics, Erasmus MC-Daniel den Hoed Cancer Center, PO Box 5201, 3008 AE, Rotterdam, The Netherlands

Correspondence: Address correspondence and reprint requests to: Alexander M. M. Eggermont, MD, PhD; E-mail: a.m.m.eggermont{at}erasmusmc.nl.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Isolated limb perfusion (ILP) is an effective treatment modality for multiple in-transit melanoma metastases confined to the limb. Recurrences after ILP, however, occur in approximately 50% of patients and are a challenge for further treatment. The efficacy of repeat ILPs to prolong local control in this patient category is evaluated in this article.

Methods: We used a prospective database in a tertiary referral center. Out of 100 tumor necrosis factor (TNF)-based ILPs with TNF and melphalan (TM-ILPs) in melanoma patients between March 1991 and July 2003, 25 repeat ILP procedures were performed in 21 patients in whom prior ILP treatment failed. All patients had bulky and/or numerous lesions and were treated with mild hyperthermic TM-ILP by using 2 to 4 mg of TNF and 10 to 13 mg/L of limb volume for the leg and arm, respectively.

Results: The complete response rate was 76%, a partial response occurred in 20%, and no change was recorded in 4%. There was no difference in the complete response rate or local toxicity between first and repeat perfusions. Local recurrence occurred in 72%; the median time to local progression was 14 months. The 5-year survival rate was 47%, which compares favorably with known survival rates of stage IIIA/AB patients. The median follow-up of the patients was 26 months.

Conclusions: Patients who experience treatment failure after previous ILP treatment respond very well to repeat perfusion, and prolonged local control can thus be obtained. The subgroup of patients qualifying for repeat ILP represents a relatively favorable biological behavior of the melanoma.

Key Words: Isolated limb perfusion • Melanoma • In-transit metastases • Extremity • TNF


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Recurrent melanoma of the limb remains a treatment challenge. Many options, from simple surgical excision to intralesional injections with cytokines to isolated limb perfusion (ILP), have been proposed. Depending on the size and number of the lesions, each modality is more or less suitable.1 ILP for melanoma has been demonstrated to be very effective in patients with multiple metastases for which surgical excision is impossible. Melphalan-based ILP is associated with complete response (CR) rates of 40% to 50% and overall response rates of 75% to 80%. When tumor necrosis factor (TNF)-{alpha} was introduced in the ILP model by Lejeune et al.,2 CR rates of 80% to 90% were reported. The first report on the European multicenter experience with TNF-based ILP in melanoma patients revealed that a significant increase in CR rates was observed in the four participating centers: 91% with TNF and melphalan (TM)-ILPs compared with a 52% CR rate for melphalan-only ILPs.3 By this treatment, disease control in the limb can be obtained in patient categories with a poor prognosis quo ad vitam.4 However, local progression in the limb after ILP with melphalan has been reported to develop in 46% to 54% of patients, and this rate was 55% in our own experience in 100 TM-ILPs, with predominantly high numbers of metastases, bulky disease, or both.5 For this patient category, treatment options are limited. Some patients, however, qualify for re-treatment of the limb when treatment fails only locally without evidence of systemic metastases. Particularly for these patients, repeat ILP might provide prolonged local control.6–8 The use of TNF in the repeat ILP is hypothesized to improve response rates in patients who do not respond or respond insufficiently to melphalan-only ILPs, but definitive proof is still lacking.7

In this article, we report on 25 TM-ILPs for locally recurrent melanoma in patients who experienced treatment failure with previous ILP treatment, both with and without TNF. Special attention is given to local and systemic progression after repeat ILP and to the locoregional toxicity of the repeat procedure.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Out of 100 TNF-based ILPs in 87 patients performed in our institution between 1991 and July 2003, 25 ILPs in 21 patients were repeat ILPs because of failure of previous ILP treatment for extensive intransit melanoma metastases. Of these 25 ILPs, 12 were performed after failure of melphalan-based ILPs performed in referring hospitals, 1 was performed after a TM-ILP elsewhere, and 12 were second (n = 10) or third (n = 2) TNF-based perfusions performed in our own institution. Tumor stage was assessed according to the M. D. Anderson staging system: 7 stage IIIA patients (only in-transit metastases; no lymph node metastases or distant metastases), 15 stage IIIAB patients (both in-transit metastases and lymph node metastases, but no distant metastases), and 3 stage IV patients (in-transit metastases and distant metastases). At the time of the second perfusion in our institution, progression of tumor stage had occurred in six patients. Local control of the intransit recurrences by surgery was impossible because of numerous lesions (>10 lesions in 21 ILPs) or the size of the lesions (≥ 40 mm in 12 ILPs). Patient and tumor characteristics of the 25 repeat ILPs in 21 patients are listed in Table 1Go.


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  		TABLE 1. Patient and tumor characteristics of 21 patients undergoing 25 repeat TM-ILPs
 
Treatment
All patients underwent an ILP of the lower extremity by an iliac (n = 15), femoral (n = 6), or popliteal (n = 4) approach. The method of ILP has been described in detail previously.9,10 In short, isolation of the limb is achieved by clamping and cannulation of the major artery and vein, connection to an oxygenated extracorporeal circuit, ligation of collateral vessels, and application of a tourniquet proximal to the site of perfusion. Once the tissue temperature has reached 38° C, recombinant TNF (Boehringer Ingelheim GmbH, Ingelheim/Rhein, Germany) is administered via the arterial line in a dose of 2 to 4 mg (mean, 3.6 mg). Tissue temperatures are stabilized between 38° C and 39.5° C, and leakage is monitored by using a precordial scintillation probe to detect leakage of radiolabeled albumen injected to the perfusion circuit.11 After 30 minutes, melphalan (L-PAM; Alkeran, Burroughs Welcome, London, UK) is added to the perfusate in a dose of 10 mg/L for leg perfusions and 13 mg/L for arm perfusions. In six ILPs performed between 1991 and 1994, interferon {gamma} (IFN) was added to the schedule according to trial prescriptions, which consisted of the subcutaneous injection of .2 mg of IFN on days – 2 and – 1 before the ILP and the injection of .2 mg of IFN during the ILP procedure into the arterial line before the administration of TNF. The median dose of melphalan was 100 mg (mean, 92.6 mg; range, 40–140 mg), and all six IFN-ILPs were performed with .2 mg of IFN. At the end of the perfusion period, a washout procedure with 2 to 4 L of a dextrane and/or electrolyte solution is performed. In patients undergoing an iliac perfusion, an iliac lymph node dissection is routinely performed. In patients with palpable nodal disease in the groin, an ilioinguinal lymph node dissection is performed in the same operative session as the ILP: the iliac lymph node dissection is performed before the ILP, and the inguinal lymph node dissection is performed immediately after the ILP.

Evaluation of Response and Toxicity
Acute local toxicity of the ILP procedure was classified according to Wieberdink et al.12: grade I, no reaction; grade II, slight erythema or edema; grade III, considerable erythema or edema with some blistering, with slightly disturbed motility permissible; grade IV, extensive epidermolysis or obvious damage to the deep tissues causing definite functional disturbance and threatening or manifest compartmental syndrome; and grade V, reaction that may necessitate amputation. Response evaluation was performed 4, 8, and 12 weeks after ILP by clinical examination, thereafter at regular 3-month intervals for the first 2 years, and subsequently at longer intervals. Response rates were reported according to World Health Organization criteria,13 in which CR is the complete disappearance of all lesions and no new areas of disease appearing within the field of ILP. Partial response (PR) was defined as a reduction of 50% to 99% of the total tumor size; no change (NC) was recorded if <50% of the total tumor size responded. Recurrence of tumor within the extremity after a CR or progression of the lesions and the appearance of new lesions after a PR or after NC was reported as local progression.

Statistical Evaluation
Estimates of survival and local/systemic progression were made by using the Kaplan-Meier method, and differences were evaluated by using the log-rank test. P values <.05 were considered to be significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Of the 25 repeat ILPs performed in our institution, 19 (76%) resulted in a CR. With an additional five ILPs with a PR, the total response rate was 96%. One patient (patient 12) showed regression of the lesions of 20% to 25%, which was recorded as NC. There was no difference in the CR rate between repeat ILPs after prior treatment elsewhere (83%) and repeat TM-ILPs in our institution (69%; P = .36). In the 12 patients who received multiple TM-ILPs in our institution, no difference in response rates was detected between first ILP (70%) and second or third ILP (75%; P = .58). Response rates for the different patient categories analyzed are listed in Table 2Go. The median time between first and repeat ILP was 25 months (range, 3–76 months).


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  		TABLE 2. Response rates
 
The median leakage of the repeat ILPs was 0% (range, 0%–13%), thus leading to absence of severe (grade IV) systemic toxicity (Table 3Go). Local toxicity was mild to moderate in all cases, with Wieberdink grade I in 12%, grade II in 60%, and grade III in 28% of the ILPs and not a singe case of grade IV toxicity. No increase in local toxicity was observed in the patients who received multiple TM-ILPs (Table 4Go).


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  		TABLE 3. Local and systemic toxicity
 

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  		TABLE 4. Patient characteristics and treatment outcome
 
Compared with our total database of TM-ILP for melanoma, which consisted of 100 ILPs, the CR rate of repeat perfusions did not differ significantly from the CR rate of patients who underwent only 1 ILP (76% vs. 68%; P = .61). Local progression occurred after 18 repeat ILPs (72%). The median time to local progression (TTLP) was 14 months for repeat perfusions versus 16 months for the overall population and 18 months for single ILPs (P = .40; Fig. 1Go). Sixteen patients developed systemic metastases during the course of follow-up; 3 already had stage IV disease at the time of repeat ILP. Time to systemic progression (TTSP) did not differ between patients receiving a single ILP (12 months) and multiple ILPs (15 months; P = .27).5 In three patients (patients 1, 2, and 5), repeat ILP (plus resection of a local recurrence on the lateral side of the proximal thigh in patient 1) contributed to sustained local control of disease in the leg. No systemic progression was observed in these patients during follow-up of 91, 129, and 72 months. The 21 patients who received multiple ILPs had a 5-year survival of 47%, compared with 28% for patients who received a single treatment (P = .05; Fig. 2Go). The median follow-up was 26 months.


Figure 1
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  		FIG. 1. Time to local progression (TTLP) for repeat versus single isolated limb perfusions (ILPs). The x-axis indicates the time (months) for repeat ILPs counted from the last procedure; the y-axis indicates the cumulative percentage.

 

Figure 2
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  		FIG. 2. Overall survival for repeat versus single isolated limb perfusions (ILPs). The x-axis indicates the time (months) for repeat ILPs counted from last procedure; the y-axis indicates the cumulative percentage.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
These results show that in a selected patient population of patients with local progression after previous ILP treatment, repeat TM-ILP is associated with excellent response rates (96%). The CR rate after TM-ILP was 76%, which compares favorably to the CR rate of single ILPs in our institution. This is in line with the scarce literature on the efficacy of repeat ILPs6–8 and is indicative of the fact that a rather favorable group of patients, mostly patients with stage IIIA disease only and with a good response to the first ILP, are considered for repeat ILPs when their disease recurs with intransit metastases. The 5-year survival rate of 47% reported in this study compares favorably to recently published4 survival rates of patients with locally advanced melanoma (23%–47%) and is again an indication of relatively mild biological behavior of the melanoma in this patient population.

The mechanism of recurrence after previous ILP treatment remains speculative. It is a common finding that in patients after a CR to the first perfusion, new recurrent in-transit metastases arise at locations different from the original lesions that went into a CR after the initial ILP. Hypothetically, this indicates that larger, wellvascularized lesions are completely eradicated but that dormant, (relatively) nonvascularized lesions are not eradicated by an ILP because of inadequate drug exposure.14

Patient selection for repeat ILP treatment is determined by the TTLP after initial ILP and the absence of systemic metastases, unless the bulkiness of the disease is directly limb threatening. Rapid disease progression after ILP is an indicator of aggressive disease and is therefore a relative contra-indication for repeat ILP treatment, because the expected response rates are low.15 The median interval between initial ILP treatment and repeat TM-ILP of 25 months, as indicated in Table 4Go, is markedly longer than the median TTLP both in this study after repeat ILP (14 months) and in our total database of 100 ILPs (16 months). In three patients (patients 13, 20, and 21), repeat TM-ILP was performed 3 to 5 months after failure of ILP with other chemotherapeutics to obtain sufficient response, and it resulted in one PR and two CRs. This shows that failure to respond to a melphalan-only isolated limb perfusion can be overcome by adding TNF, which in tumor models has been shown to enhance the uptake of melphalan by the tumor.16,17 This is in line with the observation that melphalan-only ILPs in soft tissue sarcoma patients have very poor results, whereas TM-ILPs are associated with high response rates.3 For our melanoma population, we can conclude that, apart from the three patients with rapid failures after a melphalan-only isolated limb perfusion, the melanoma of patients who qualify for repeat treatment is relatively indolent. This observation is sustained by the significant difference in overall survival between repeat and single ILPs.

Whether to consider a patient for repeat ILP should be influenced by the stage of disease at first ILP. We found in our experience with 100 TM-ILPs that curves of TTLP and TTSP virtually overlap in stage IIIAB disease, whereas in patients with stage IIIA disease, the median TTSP was 55 months at a median TTLP of 18 months. This difference makes patients with stage IIIA disease with local progression much better candidates for repeat ILP than those with stage IIIAB disease.5

We found toxicity after repeat TM-ILPs to be mild to moderate in all procedures. Compared with the first ILP, repeat TM-ILP did not increase local toxicity, in contrast to a previous report with melphalan alone.6 In this study, however, more intensive schedules were used for the repeat ILP (higher tissue temperatures and ILPs at short intervals).6 Other, smaller, studies do not report on increased local or systemic toxicity.7,8 On the basis of these data, we state that the use of mild hyperthermic TM-ILP for repeat perfusion is safe. The median leakage to the systemic compartment was 0% in these 25 repeat ILPs, just as in our overall experience with TM-ILP in more than 350 patients. TM-ILP is safe provided that adequate leakage monitoring is ensured and postoperative fluid management is generous to deal adequately with the TNF-mediated transient decrease in the peripheral vascular resistance after ILP.18,19 Moreover, the safety of the procedure is such that, in our opinion, there should be no age limit. Especially in limb-threatening disease, limb salvage is of prime importance, and this treatment should not be withheld from the elderly, as we have demonstrated in our extensive experience in patients >75 years old.20

In conclusion, repeat TM-ILP is a valuable treatment option in patients with local progression after previous ILP treatment. In patients with bulky or numerous lesions that cannot be managed with surgery, repeat TM-ILP provides excellent disease control. Especially patients with recurrences after ILP for stage IIIA disease and patients with a long interval between initial and repeat ILP, who constitute a subcategory of melanoma patients with relatively favorable characteristics, profit from this treatment. Moreover, patients with no response or rapid progression after a melphalan-only ILP can still respond with a CR to a TM-ILP.

Received for publication March 19, 2004. Accepted for publication March 22, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Eggermont AM. Treatment of melanoma in-transit metastases confined to the limb. Cancer Surv 1996;26:335–49.[Medline]
  2. Lienard D, Ewalenko P, Delmotte JJ, et al. High-dose recombinant tumor necrosis factor alpha in combination with interferon gamma and melphalan in isolation perfusion of the limbs for melanoma and sarcoma. J Clin Oncol 1992;10:52–60.
  3. Lejeune F, Lienard D, Eggermont A, et al. Rationale for using TNF alpha and chemotherapy in regional therapy of melanoma. J Cell Biochem 1994;56:52–61.[Medline]
  4. Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 2001;19:3622–34.[Abstract/Free Full Text]
  5. Grünhagen DJ, Brunstein F, Graveland WJ, et al. One hundred consecutive isolated limb perfusions with TNF-alpha and melphalan in melanoma patients with multiple in-transit metastases. Ann Surg 2004;240:939–48.[CrossRef][Medline]
  6. Klop WM, Vrouenraets BC, van Geel BN, et al. Repeat isolated limb perfusion with melphalan for recurrent melanoma of the limbs. J Am Coll Surg 1996;182:467–72.[Medline]
  7. Bartlett DL, Ma G, Alexander HR, et al. Isolated limb reperfusion with tumor necrosis factor and melphalan in patients with extremity melanoma after failure of isolated limb perfusion with chemotherapeutics. Cancer 1997;80:2084–90.[CrossRef][Medline]
  8. Feldman AL, Alexander HR Jr, Bartlett DL, et al. Management of extremity recurrences after complete responses to isolated limb perfusion in patients with melanoma. Ann Surg Oncol 1999;6:562–7.[Abstract]
  9. Eggermont AM, Schraffordt Koops H, Klausner JM, et al. Isolated limb perfusion with tumor necrosis factor and melphalan for limb salvage in 186 patients with locally advanced soft tissue extremity sarcomas. The cumulative multicenter European experience. Ann Surg 1996;224:756–64; discussion 764–5.[CrossRef][Medline]
  10. Eggermont AM, Schraffordt Koops H, Lienard D, et al. Isolated limb perfusion with high-dose tumor necrosis factor-alpha in combination with interferon-gamma and melphalan for nonresectable extremity soft tissue sarcomas: a multicenter trial. J Clin Oncol 1996;14:2653–65.[Abstract/Free Full Text]
  11. Klaase JM, Kroon BB, van Geel AN, et al. Systemic leakage during isolated limb perfusion for melanoma. Br J Surg 1993;80:1124–6.[Medline]
  12. Wieberdink J, Benckhuysen C, Braat RP, et al. Dosimetry in isolation perfusion of the limbs by assessment of perfused tissue volume and grading of toxic tissue reactions. Eur J Cancer Clin Oncol 1982;18:905–10.[CrossRef][Medline]
  13. WHO Handbook for Reporting Results of Cancer Treatment. Geneva: World Health Organization, 1979.
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  15. Polk HC Jr, Edwards MJ. Post-perfusion recurrent melanoma. Ann Surg Oncol 1999;6:524.[Medline]
  16. de Wilt JH, ten Hagen TL, de Boeck G, et al. Tumour necrosis factor alpha increases melphalan concentration in tumour tissue after isolated limb perfusion. Br J Cancer 2000;82:1000–3.[CrossRef][Medline]
  17. de Wilt JH, Manusama ER, van Tiel ST, et al. Prerequisites for effective isolated limb perfusion using tumour necrosis factor alpha and melphalan in rats. Br J Cancer 1999;80:161–6.[CrossRef][Medline]
  18. Stam TC, Swaak AJ, de Vries MR, et al. Systemic toxicity and cytokine/acute phase protein levels in patients after isolated limb perfusion with tumor necrosis factor-alpha complicated by high leakage. Ann Surg Oncol 2000;7:268–75.[Abstract]
  19. Vrouenraets BC, Kroon BB, Ogilvie AC, et al. Absence of severe systemic toxicity after leakage-controlled isolated limb perfusion with tumor necrosis factor-alpha and melphalan. Ann Surg Oncol 1999;6:405–12.[Abstract]
  20. van Etten B, van Geel AN, de Wilt JH, Eggermont AM. Fifty tumor necrosis factor-based isolated limb perfusions for limb salvage in patients older than 75 years with limb-threatening soft tissue sarcomas and other extremity tumors. Ann Surg Oncol 2003;10:32–7.[Abstract/Free Full Text]



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