Latest Review Date:  April 2024

Category:  Surgery                                                                 

POLICY:

Isolated limb perfusion with melphalan may be considered medically necessary when used as a therapeutic treatment of local recurrence of non-resectable melanoma (i.e., satellite lesions or “in transit” melanoma).

Isolated limb perfusion with melphalan is considered not medically necessary when used for the following indications:

• As an adjuvant treatment of surgically treated primary malignant melanoma with no clinical evidence of disease.
• As an adjuvant treatment of surgically treated locally recurrent melanoma with no other evidence of disease.
• In conjunction with tumor necrosis factor or interferon gamma for primary malignant melanoma, locally recurrent melanoma with no other evidence of disease or local recurrence of non-resectable melanoma.

Isolated limb perfusion in conjunction with hyperthermia is considered investigational.

Isolated limb infusion (ILI) with melphalan may be considered medically necessary for the therapeutic treatment of local recurrence of nonresectable melanoma (i.e., satellite lesions or “in transit” melanoma).

Isolated limb infusion in the treatment of melanoma for all other indications is considered not medically necessary.

DESCRIPTION OF PROCEDURE OR SERVICE:

Isolated limb perfusion (ILP) is a method of drug delivery that is designed to deliver high local doses of chemotherapeutic agents to isolated anatomic regions 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 the cytokine tumor necrosis factor alpha (TNF-alpha) and/or interferon gamma (IFN-gamma).  ILP as a treatment of melanoma has been investigated in two general settings—either as adjuvant treatment after all clinical disease has been surgically resected or as therapeutic treatment for patients with surgically unresectable disease.

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.

In isolated limb infusion (ILI), catheters are inserted percutaneously into the axial artery and vein of the affected limb and a pneumatic tourniquet is inflated proximally.  Cytotoxic agents are then infused through the arterial catheter and circulated with a syringe for 15 to 20 minutes after which the limb is flushed with a liter of Hartman’s solution.  Progressive hypoxia occurs, but normothermia is maintained.  This procedure differs from ILP primarily by avoiding the use of an extracorporeal circulation system, making it less expensive, requiring fewer medical personnel, and reducing the total operating room time.

KEY POINTS:

The most recent literature review was updated through April 10, 2024.

Summary of Evidence

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. Large ILP case series have consistently reported impressive complete response rates compared to systemic chemotherapy and there is no alternative therapy that would provide a meaningful comparison.

Except for use of ILI in treatment of local recurrence of nonresectable melanoma, ILI in the treatment of melanoma is considered investigational due to lack of sufficient data concerning outcomes.

Practice Guidelines and Position Statements

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 April 2024.

The National Cancer Comprehensive Cancer Network (NCCN) v.2.2024 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).

KEY WORDS:

Isolated limb perfusion, ILP, melphalan, malignant melanoma, tumor necrosis factor, interferon gamma, hyperthermia, isolated limb infusion, ILI

APPROVED BY GOVERNING BODIES:

TNF is not FDA approved for any indication

Melphalan is FDA approved

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group-specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP: Special benefit consideration may apply. Refer to member’s benefit plan.

CURRENT CODING: 

CPT codes:                 

HCPCS:           

REFERENCES:

1. Balch CM, Houghton AN, Sober AJ, Soong S.  Cutaneous melanoma, 1998, St. Louis, MO, Quality Medical Publishers, pp. 282-299.
2. Bartlett DL, 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, December 1997; 80(11): 2084-2090.
3. Beasley GM, Caudle A, Petersen RP, et al.  A multi-institutional experience of isolated limb infusion:  Defining response and toxicity in the US.  J Am Coll Surg, May 2009; 208(5): 706-715.
4. Beasley GM, Petersen RP, Yoo J, et al.  Isolated limb infusion for in-transit malignant melanoma of the extremity:  A well-tolerated but less effective alternative to hyperthermic isolated limb perfusion.  Ann Surg Oncol, August 2008; 15(8): 2195-2205.
5. Brobeil A.  Efficacy of hyperthermic isolated limb perfusion for extremity-confined recurrent melanoma, Annals of Surgical Oncology, June 1998; 5(4): 376-383.
6. 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, September 2006; 24(25): 4196-4201. (Abstract)
7. Eggermont AM, et al.  Current uses of isolated limb perfusion in the clinic and a model system for new strategies, Lancet Oncology, July 2003; 4(7): 429-437.
8. Eggermont AM, et al.  Isolated limb perfusion for extremity soft tissue sarcomas, intransit metastases, and other unresectable tumors:  Credits, debits, and future perspectives, Current Oncology Report, July 2001; 3(4): 359-367.
9. Fraker DL, et al.  Treatment of patients with melanoma of the extremity using hyperthermic isolated limb perfusion with melphalan, tumor necrosis factor and interferon gamma :  Results of a tumor-necrosis factor dose escalation study, Journal of Clinical Oncology, February 1996; 14(2): 479-489.
10. Fraker DL.  Management of in-transit melanoma of the extremity with isolated limb perfusion, Current Treatment Options in Oncology 2004; 5: 173-184.
11. Gershenwald JE.  Surgical clinical trials in melanoma, Surgical Clinics of North America, April 2003, Vol. 83, No. 2.
12. Ghussen F, et al.  The roll of regional hyperthermic cytostatic perfusion in the treatment of extremity melanoma, Cancer, February 1988; 61(4): 654-659.
13.  Hafstrom L, et al.  Regional hyperthermic perfusion with melphalan after surgery for recurrent malignant melanoma of the extremities, Journal of Clinical Oncology 1991; 9(12): 2091-2094.
14. IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press.
15. Kapteijn BA.  Results of regional isolated perfusion for locally inoperable melanoma of limbs, Melanoma Research, April 1994; 4(2): 135-138.
16. Klaase JM, et al.  A retrospective comparative study evaluating the results of mild hyperthermia versus controlled normothermic perfusion for recurrent melanoma of the extremities, European Journal of Cancer, January 1995; 31A(1): 58-63.
17. Klaase JM, et al.  Limb recurrence-free interval and survival in patients with recurrent melanoma of the extremities treated with normothermic isolated perfusion, Journal of the American College of Surgeons, June 1994; 178(6): 564-572.
18. Koops HS, et al.  Prophylactic isolated limb perfusion for localized, high-risk limb melanoma:  Results of a multicenter randomized phase III trial.  European Organization for Research and Treatment of Cancer.  Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593, Journal of Clinical Oncology, September 1998; 16(9): 2906-2912.
19. Krementz ET, et al.  Regional chemotherapy for melanoma.  A 35 year experience, Annals of Surgery, October 1994; 220(4): 520-534.
20. Lens MB and Dawes M.  Isolated limb perfusion with melphalan in the treatment of malignant melanoma of the extremities:  A systematic review of randomized controlled trials, The Lancet Oncology, June 2003, Vol. 4, No. 6.
21. Lienard D, 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, Journal of Clinical Oncology, January 1992; 10(1): 52-60.
22. Lienard D, et al.  Isolated limb perfusion in primary and recurrent melanoma:  Indications and results, Seminars in Surgical Oncology, April-May 1998; 14(3): 202-209.
23. Lienard D, 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 multicenter randomized phase II study, Melanoma Research, October 1999; 9(5): 491-502.
24. Lienard D, et al.  Isolated perfusion of the limb with high-dose tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and melphalan for melanoma stage III.  Results of a multicenter pilot study, Melanoma Research, March 1994; 4 Supplement 1: 21-26.
25. Ma D and Ariyan S.  The use of isolated limb perfusion to manage recurrent malignant melanoma, Clinics in Plastic Surgery, July 2000; 27(3): 441-450, ix.Melanoma: Cutaneous, Version 2.2023-March 10, 2023 www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdf
26. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology.
27. Noorda EM, et al.  Isolated limb perfusion prolongs the limb recurrence-free interval after several episodes of excisional surgery for locoregional recurrent melanoma, Annals of Surgical Oncology, May 2004; 11(5): 491-499.
28. Noorda EM, 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): 395-399.
29. Noorda EM, et al.  Prognostic factors for survival after isolated limb perfusion for malignant melanoma, European Journal of Surgical Oncology, December 2003; 29(10): 916-921.
30. Noorda EM, et al.  Safety and efficacy of isolated limb perfusion in elderly melanoma patients, Annals of Surgical Oncology, December 2002; 9(10): 968-974.
31. Pitts JM and Maloney ME.  Therapeutic advances in melanoma, Dermatologic Clinics, January 2000, Vol. 18, No. 1, pp. 157-167.
32. 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, February 2004; 11(2): 173-177.
33. Shapiro RL.  Surgical approaches to malignant melanoma:  Practical guidelines, Dermatologic Clinics, October 2002, Vol. 20, No. 4.
34. Storm FK, et al.  Value of therapeutic hyperthermic limb perfusion in advanced recurrent melanoma of the lower extremity, American Journal of Surgery, July 1985; 150(1): 32-35.
35. Swetter, SM, Wells, MJ, Albertini, JG, Elston, DM, Burg, G.  Cutaneous Melanoma Treatment & Management, March 22, 2022. www.emedicine.com/derm/topic257.htm.
36. Thompson JF, et al.  Frequency and duration of remission after isolated limb perfusion for melanoma, Archives of Surgery, August 1997; 132(8): 903-907.
37. Thompson JF, Kam PC, Waugh RC and Harman CR.  Isolated limb infusion with cytotoxic agents:  A simple alternative to isolated limb perfusion.  Semin Surg Oncol, Apr-May 1998; 14(3): 238-247.
38. Van Ginkel RJ, Limburg PC, 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.
39. 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): 390-4.
40. Vrouenraets BC, et al.  Long term functional morbidity after mild hyperthermic isolated limb perfusion with melphalan, European Journal of Surgical Oncology, October 1999; 25(5): 503-508.
41. Vrouenraets BC, et al.  Relation between limb toxicity and treatment outcomes after isolated limb perfusion for recurrent melanoma, Journal of the American College of Surgeons, May 1999; 188(5): 522-530.
42. Vrouenraets BC, et al.  Thirty-five years of isolated limb perfusion for melanoma:  Indications and results, British Journal of Surgery, October 1996; 83(10): 1319-1328.
43. Zogakis TG, et al.  Factors affecting survival after complete response to isolated limb perfusion in patients with in-transit melanoma, Annals of Surgical Oncology, December 2001; 8(10): 771-778.

POLICY HISTORY:

Medical Policy Group, July 2004 (2)

Medical Policy Administration Committee, August 2004

Available for comment August 11-September 24, 2004

Medical Policy Group, July 2007 (1)

Medical Policy Group, July 2010 (1): Policy updated, Key points updated, coverage statement updated with ILI

Medical Policy Administration Committee, June 2010

Available for comment June 18-August 2, 2010

Medical Policy Group, September 2012 (3): Active Policy but no longer scheduled for regular literature reviews and updates.

Medical Policy Group, October 2013 (3): Removed ICD-9 Diagnosis/Procedure codes; no change to policy statement.

Medical Policy Group, January 2020 (2): Reviewed by consensus. Updates to Description, Key Points, and References. No new published peer-reviewed literature available that would alter the coverage statement in this policy.

Medical Policy Group, August 2021 (2): Reviewed by consensus. Updates to Description. Updated Policy section to remove “investigational” wording. No new published peer-reviewed literature available that would alter the coverage statement in this policy.

Medical Policy Group, April 2022 (2): Reviewed by consensus. Updates to Key Points. No new published peer-reviewed literature available that would alter the coverage statement in this policy.

Medical Policy Group, March 2023 (2): Reviewed by consensus. Updates to Key Points, Benefit Application and References.  No new published peer-reviewed literature available that would alter the coverage statement in this policy.

Medical Policy Group, April 2024 (2): Reviewed by consensus. Updates to Key Points; Practice Guidelines and Position Statements, Benefit Application, and References.  No new published peer-reviewed literature available that would alter the coverage statement in this policy.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.