Isolated limb perfusion (ILP) is a method of drug delivery that is designed to deliver high local doses of chemotherapy while avoiding systemic toxicity. It has been investigated primarily as a treatment of malignant melanoma arising in the extremities. ILP involves the following steps: 1) mobilization and placement of venotomy and arteriotomy catheters into the major blood vessels (axillary, brachial, iliac, or popliteal artery and vein) proximal to the tumor; 2) isolation of the limb via a tourniquet; and 3) perfusion of a chemotherapeutic drug via an extracorporeal circulation system into the affected extremity. Perfusion lasts for approximately 60 minutes. Melphalan is the drug typically used, but more recently melphalan has been combined with tumor necrosis factor (TNF) and/or interferon gamma. ILP has also been performed in conjunction with mild hyperthermia based on the theoretical rationale that heat may potentiate the tumor-killing effect of melphalan. Hyperthermia is performed by warming the perfusate and by wrapping the treated extremity in a warming blanket. Target tissue temperature is typically 39 to 40 degrees Celsius.

ILP as a treatment of melanoma has been investigated in 2 general settings—either as an adjuvant treatment after all clinical disease has been surgically resected or as a therapeutic treatment for patients with surgically unresectable disease. The adjuvant setting can be further broken down into its use after initial resection of primary melanoma considered to be at high risk for recurrence or its use after resection of local recurrences, frequently referred to as satellite lesions or “in-transit” melanoma.

When used as an adjuvant treatment of surgically treated primary malignant melanoma with no clinical evidence of disease, isolated limb perfusion with melphalan is considered not medically necessary.

When used as an adjuvant treatment of surgically treated locally recurrent melanoma with no other evidence of disease, isolated limb perfusion with melphalan is considered investigational.

When used as a therapeutic treatment of local recurrence of nonresectable melanoma (i.e., satellite lesions or “in transit” melanoma), isolated limb perfusion with melphalan may be considered medically necessary.

Isolated limb perfusion in conjunction with hyperthermia is considered investigational.

Isolated limb perfusion using melphalan in conjunction with tumor necrosis factor or interferon gamma is considered investigational.

Patients typically undergo 1 treatment with isolated limb perfusion. Some patients with incomplete responses after the first procedure may undergo a second course of treatment.

Isolated limb perfusion is a specialized procedure that may require referral to out-of-network facilities.

Coding

CPT code 77600 describes the use of hyperthermia, considered investigational, as a component of isolated limb perfusion.

Isolated limb perfusion consists of 2 components: insertion/removal of the catheters for delivery of the chemotherapy and the actual delivery of the chemotherapy.

36823: Insertion of arterial and venous cannula(s) for isolated extracorporeal circulation and regional chemotherapy perfusion to an extremity, with or without hyperthermia, with removal of cannulas(s) and repair of arteriotomy and venotomy sites.

The note accompanying this code indicates that CPT code 36823 is intended to be global, i.e., it includes the actual delivery of chemotherapy in addition to insertion and removal of the cannula. In the past, some providers may have billed separately for the actual infusion of chemotherapy (i.e., CPT codes 96409, 96411, 96413, 96415, 96416, 96417, 96420, 96422, 96423, 96425); however, the note explicitly states that these codes should not be reported separately in conjunction with CPT code 36823.

BlueCard/National Account Issues

No applicable information

Isolated limb perfusion (ILP) has been used in either the adjuvant or therapeutic setting. 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. (1) 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.

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, (2) the results were so inconsistent with prior experience with ILP that researchers remain skeptical about the results of this study. (3) The other randomized study was a small single-institution study that did not report a statistically significant improvement in overall survival. (4) 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 investigational.

As pointed out in the 1992 TEC Assessment, no randomized controlled trials are focusing currently 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%. (3) According to the authors, no randomized controlled trials are available, because currently no alternative therapy would provide a meaningful comparison to ILP with melphalan. (3) In this population of patients with few treatment options, ILP with melphalan is currently considered the gold standard. Instead, research has focused on ways to enhance the results of ILP with melphalan. Recent research has been interested in 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. (5) 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. (6) No significant difference was noted between the 2 groups in terms of complete or overall response rate. In this country, a Phase III randomized trial was initiated to compare ILP with melphalan alone and ILP with melphalan, TNF, and interferon-gamma; final results have not yet been published. Two multi-institutional studies are currently being initiated; both studies will compare ILP with melphalan alone or in combination with TNF. Data also suggest that ILP using TNF is an effective palliative treatment for patients with bulky melanomas causing pain, decreased mobility, or skin breakdown. (3) 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 investigational. Similarly, the additional benefit of interferon gamma as part of the ILP drug regimen has not been validated and is considered investigational.

Mild hyperthermia is often used in conjunction with ILP. 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. (3)

2005 Update

Updated literature searches of the MEDLINE database through May 2005 did not identify any published literature that would change the above conclusions; therefore, the policy statement remains unchanged. There continues to be interest in using TNF in conjunction with melphalan as the infusate. (7-9) However, final results of the randomized studies of TNF mentioned here have not yet been published. In addition, TNF is not FDA approved for any indication. 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. (10) 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 (65%) patients with a 5-year limb recurrence-free interval of 63%. While these results are promising in extensive disease, this approach requires 2 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. (9) 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 (11) 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.

2006 Update

An updated literature search of the MEDLINE database from 2005 through May 2006 identified no new clinical trial publications. Therefore, the policy statement is unchanged.

2008 Update
An updated literature search of the MEDLINE database from May 2006 through June 2008 did not identify any published literature that would change the policy statement.
The results of a randomized, multicenter trial were published in which patients with locally advanced extremity melanoma received melphalan-based hyperthermic isolated limb perfusion (HILP) treatment with randomization as to whether they received tumor necrosis factor alpha (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 HILP 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. The conclusions of this trial are consistent with the current policy statement. The current policy statements are unchanged.
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 June 2008.
The National Comprehensive Cancer Network (NCCN) guidelines for unresectable in-transit melanoma include hyperthermic limb perfusion with melphalan; this is a category 2-B recommendation (meaning the recommendation is based on “lower level evidence” and “nonuniform NCCN consensus” without major disagreement). (13)
Physician Specialty Society and Academic Medical Center Input
In response to requests, responses were received from 2 academic medical centers while this policy was under review. While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted. One academic center declined comment, indicating they do not perform this procedure because it is so specialized but instead refer potential candidates (1 – 2 patients per year) to specific centers. The reviewer from the second center agreed with the policy conclusions. Citing reference 12 in this policy, the reviewer commented that there are no data from trials that address whether hyperthermia contributes to the effect of ILP with melphalan.

References:

1. Koops H, Vaglini M, Kroon BB et al. Value of prophylactic isolated limb perfusion for stage I high-risk malignant melanoma. A randomized Phase III trial. Melanoma Res 1997; (suppl1):534.
2. Ghussen F, Kruger I, Groth W et al. The role of regional hyperthermic cytostatic perfusion in the treatment of extremity melanoma. Cancer 1988; 61(4):654-9.
3. Balch CM, Houghton AN, Sober AJ et al. (eds.). Cutaneous Melanoma. 3rd edition. St. Louis, MO: Quality Medical Publishers, 1998. pp. 282-99.
4. Hafstrom L, Rudenstam CM, Blomquist E et al. Regional hyperthermic perfusion with melphalan after surgery for recurrent malignant melanoma of the extremities. Swedish Melanoma Study Group. J Clin Oncol 1991; 9(12):2091-4.
5. Leinard D, Ewalenko P, Delmotte J 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(1): 52-60.
6. Lienard D, Eggermont AM, Koops HS et al. Isolated limb perfusion with tumour necrosis factor-alpha and melphalan with or without interferon-gamma for the treatment of in-transit melanoma metastases: a multicentre randomized phase II study. Melanoma Res 1999; 9(5):491-502.
7. Vrouenraets BC, Eggermont AM, Hart AA et al. Regional toxicity after isolated limb perfusion with melphalan and tumor necrosis factor-alpha versus toxicity after melphalan alone. Eur J Surg Oncol 2001; 27(4):390-5.
8. Van Ginkel RJ, Limburg PC, Piers DA et al. Value of continuous leakage monitoring with radioactive iodine-131-labeled human serum albumin during hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan. Ann Surg Oncol 2002; 9(4):355-63.
9. Rossi CR, Foletto M, Mocellin S et al. Hyperthermic isolated limb perfusion with low-dose tumor necrosis factor-alpha and melphalan for bulky in-transit melanoma metastases. Ann Surg Oncol 2004; 11(2):173-7.
10. Noorda EM, Vrouenraets BC, Nieweg OE et al. Long-term results of a double perfusion schedule using high dose hyperthermia and melphalan sequentially in extensive melanoma of the lower limb. Melanoma Res 2003; 13(4):395-9.
11. Noorda EM, Vrouenraets BC, Nieweg OE et al. Noorda EM, Vrouenraets BC, Nieweg OE et al. Isolated limb perfusion: what is the evidence for its use? Ann Surg Oncol 2004; 11(9):837-45.
12. Cornett WR, McCall LM, Petersen RP et al. Randomized multicenter trial of hyperthermic isolated limb perfusion with melphalan alone compared with melphalan plus tumor necrosis factor: American College of Surgeons Oncology Group Trial Z0020. J Clin Oncol 2006; 24(25):4196-201.
13. Melanoma. Clinical Practice Guidelines in Oncology. National Comprehensive Cancer Network. V.2.2009 http://www.nccn.org/professionals/physician_gls/PDF/melanoma.pdf (Accessed Nov 26, 2008).

Chemotherapy, Isolated Regional Perfusion
Isolated Limb Perfusion
Melanoma, Malignant, of the Extremity
Perfusion, Isolated Limb