Isolated Limb Perfusion (ILP)/Isolated Limb Infusion (ILI)
ILP with melphalan, with or without hyperthermia OR ILI with melphalan, with or without hyperthermia, may be considered medically necessary when used as a therapeutic treatment of local recurrence or regional metastases of non-resectable melanoma (i.e., satellite lesions or “in transit” melanoma).
ILP with melphalan, with or without hyperthermia OR ILI with melphalan, with or without hyperthermia, is considered not medically necessary when used as an adjuvant treatment of surgically treated primary malignant melanoma with no clinical evidence of disease.
ILP with melphalan, with or without hyperthermia OR ILI with melphalan, with or without hyperthermia, is considered experimental, investigational and unproven when used:
- As an adjuvant treatment of surgically treated locally recurrent melanoma with no other evidence of disease, OR
- In conjunction with tumor necrosis factor (TNF) or interferon gamma.
Isolated limb perfusion (ILP) and isolated limb infusion (ILI) have been used in the adjuvant and therapeutic settings.
Therapeutic treatment of local recurrence of nonresectable melanoma (i.e., satellite lesions or in transit melanoma
No randomized, controlled trials are currently focusing on the therapeutic use of ILP as a treatment of locally recurrent melanoma that cannot be surgically resected. However, large case series have consistently reported impressive complete response rates, compared to systemic chemotherapy. For example, as summarized by Balch et al, complete response rates range from 40%–60%, with an overall response rate of 80%. (2) According to the authors, no randomized, controlled trials are available, because currently no alternative therapy would provide a meaningful comparison to ILP with melphalan. In this population of patients with few treatment options, ILP with melphalan is currently considered the gold standard.
As with ILP, no data from randomized, controlled trials exist to assess the efficacy of ILI. Introduced by Thompson and colleagues, they first reported on case series of 82 patients treated with ILI for melanoma with 6 months of follow-up. (1) Complete response (CR) was reported for 39% and partial response (PR) for 52% following a single ILI session; after two sessions CR was 45% and PR was 42%. Beasley and colleagues published papers on two data sets. (3,4) The first, in 2008, was a database study of 120 regionally treated melanoma patients (over the time frame of 1995–2007); 58 patients received ILI and 54 patients were treated with ILP and variables were compared using Chi-square analysis. Response was defined at 3 months using the Response Evaluation Criteria in Solid Tumors (RECIST). Complete, partial, and no response was seen in 30%, 14%, and 56% of ILI recipients, respectively, versus 57%, 31%, and 12% (p<0.0001) of those getting ILP, respectively. ILP recipients did, however, have a greater number of grade 3 or greater toxicities: 18% vs. 32%, respectively (p=0.037). (3) The second study published in 2009 looked at response and toxicity associated with ILI only. Patient characteristics from 162 ILI procedures performed at 8 institutions (over the time frame of 2001–2008) were compared with Chi-square and t-statistics. Complete, partial, and no response was seen in 31%, 33%, and 36%, respectively. Thirty-six percent had grade 3 or greater toxicity, with one toxicity-related amputation. The authors reporting the first multi-institutional analysis of ILI concluded that the procedure is a reasonable alternative to hyperthermic isolated limb perfusion in the management of advanced extremity melanoma. (4)
Few centers in the United States have any sizable experience with ILI. The majority of procedures have been performed in Australia at the Sydney Melanoma Unit (SMU), where upward of 300 procedures have been performed. At SMU, they report a better overall response rate than has been reported by Beasley and colleagues (84% vs. 64%). ILI is a rare procedure with a learning curve for the technique, which can contribute to response variation. Many centers in the Beasley study had completed less than 10 ILI procedures. (4) At SMU, response was measured at a median time of 1.4 months, whereas in the United States, response is measured at 3 months, also potentially contributing to the difference in rates.
Due to the small numbers, inability to blind to treatment assignment, and potentially the lack of good comparators, there may never be a randomized control trial of either ILI or ILP. The body of evidence for these procedures could however be strengthened by prospectively designed studies with standardized response data, allowing for comparisons between trials and centers.
Of note, use of ILI in the treatment of melanoma is considered investigational (except for use of ILI in treatment of local recurrence of nonresectable melanoma) due to lack of sufficient data concerning outcomes.
Adjuvant treatment of surgically treated locally recurrent melanoma with no other evidence of disease
Two randomized, controlled trials have focused on the adjuvant use of ILP in patients with surgically resected recurrent satellite lesions or in transit disease. While 1 of these trials reported a highly significant improvement in overall survival, (5) the results were inconsistent with prior experience with ILP and researchers remain skeptical about the results of this study. (2) The other randomized study was a small single-institution study that did not report a statistically significant improvement in overall survival. (6) The lack of definitive data either proving or disproving the role of ILP in this adjuvant setting provides the rationale for considering this role of ILP as experimental, investigational and unproven.
Isolated limb perfusion using melphalan in conjunction with tumor necrosis factor, interferon gamma or hyperthermia
Current research is focused on ways to enhance the results of ILP with melphalan such as the use of tumor necrosis factor (TNF) or interferon gamma along with melphalan. An initial European Phase II trial combining TNF with melphalan reported a complete response rate of 90% among 28 patients, with only 2 recurrences within 14 months. (7) These results were considered so impressive that it was considered unethical to withhold TNF in any randomized trial. A subsequent randomized trial from the same group of investigators studied the use of ILP with TNF and melphalan (2-drug regimen) with and without additional interferon gamma (3-drug regimen) in 64 patients with in-transit metastases. (8) No significant difference was noted between the two groups in terms of complete or overall response rate. Continued interest in the use of TNF in conjunction with melphalan as the infusate prompted a series of studies. (9-11) In 2008, the results of a randomized, multicenter trial were published in which patients with locally advanced extremity melanoma received melphalan-based hyperthermic ILP treatment with randomization as to whether they received TNF alpha as well. (12) The intervention was completed in 124 of 133 enrolled patients, and 116 of the patients had data available at 3 months. The primary clinical endpoint of the study was tumor response, assessed at 3 months. Secondary objectives included evaluation of treatment toxicity, local recurrence-free survival, regional disease symptoms, and overall survival. A response to treatment at 3 months was seen in 64% of patients in the melphalan-alone group versus 69% in the melphalan plus TNF-alpha group (p=0.435), with a complete response in 25% of the melphalan alone and 26% of the melphalan plus TNF-alpha patients (p=0.890). The authors concluded that the addition of TNF alpha to melphalan in the treatment of locally advanced extremity melanoma with hyperthermic ILP did not demonstrate a significant difference in short-term response rates. In addition, the TNF-alpha plus melphalan regimen was associated with a higher complication rate.
Mild hyperthermia is often used in conjunction with ILP, as in the cited clinical trial. However, no published controlled trials compare the outcomes of ILP with and without hyperthermia. Retrospective analyses of case series suggest that no significant improvement occurs when hyperthermia is added to the ILP regimen. (2) Noorda and colleagues examined the use of true hyperthermia ILP (in the range of 42–43 degrees Celsius) used sequentially with normothermic ILP with melphalan in 17 patients with grossly recurrent limb melanoma. (13) With this approach, the maximum tolerable dosages can be applied with each treatment sequentially in attempts to avoid the toxicity that occurs with simultaneous use. The authors report complete remission in 11 patients (65%) with a 5-year limb recurrence-free interval of 63%. While these results are promising in extensive disease, this approach requires two surgical procedures within a 1- to 2-week timeframe, doubling surgical risk. Also, larger studies are needed to determine whether sequential true hyperthermia ILP and ILP with melphalan is superior to ILP with melphalan alone. In a study of 20 patients with in-transit melanoma metastases treated with hyperthermia ILP with melphalan and low-dose TNF alpha, Rossi et al reported disease-free survival in 6 patients while 7 patients experienced local and/or distant disease recurrence and 7 patients died of disease progression at 18-month follow-up. (11) The authors found this approach to have acceptable local toxicity and outcomes comparable to treatment with more toxic levels of cytokines. However, this study does not address questions of hyperthermia versus normothermia ILP nor does it address ILP with melphalan with or without TNF alpha. Noorda and colleagues (14) concluded ILP with melphalan (with or without TNF alpha and interferon gamma) is appropriate for local recurrence of unresectable melanoma. However, ILP with melphalan could not be recommended as an adjuvant treatment for primary or locally recurrent melanoma. The conclusions of this meta-analysis are consistent with the policy statements here.
Data also suggest that ILP using TNF is an effective palliative treatment for patients with bulky melanomas causing pain, decreased mobility, or skin breakdown. (2) However, at the present time, TNF is not a drug approved by the U.S. Food and Drug Administration (FDA) for any indication, and thus, on this basis, the use of TNF in an ILP procedure is considered experimental, investigational and unproven. Similarly, the additional benefit of interferon gamma as part of the ILP drug regimen has not been validated and is considered experimental, investigational and unproven.
Adjuvant treatment of surgically treated primary malignant melanoma with no clinical evidence of disease
In the adjuvant setting in patients with complete resection of the primary lesion without evidence of metastatic disease, ILP has been the subject of numerous inconclusive case control trials using either matched or historical controls. Results of a large international randomized clinical trial of adjuvant ILP as an adjuvant treatment in patients with high-risk primary melanoma (i.e., >1.5 mm in thickness) have been published. (15) While the incidence of local recurrence decreased in the treatment group, the overall survival was unchanged. The presence of negative data from a large randomized trial provides the rationale for considering this adjuvant role of ILP as not medically necessary.
Current Clinical Trials and Guidelines
A search of the National Cancer Institute’s Physician Data Query database returned no active phase III trials involving isolated limb perfusion and melanoma, as of November 2009.
The National Comprehensive Cancer Network (NCCN) guidelines for unresectable in-transit melanoma or in-transit recurrence include hyperthermic limb perfusion or infusion with melphalan; these are category 2-B recommendation (meaning the recommendation is based on “lower level evidence” and “nonuniform NCCN consensus” without major disagreement). (16)
A search of peer reviewed literature through May 2012 was performed.
For Stage III in-transit melanoma, and for local, satellite, and/or in-transit recurrence the National Comprehensive Cancer Network (NCCN) guidelines include hyperthermic perfusion/infusion with melphalan as a possible treatment option. These are category 2B recommendations, meaning the recommendation is “based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate”. (18)
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