Subject:
Isolated Limb Perfusion/Isolated Limb Infusion for Malignant Melanoma
Description:
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IMPORTANT NOTE:
The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.
Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.
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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 on an investigational basis 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 two 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.
Similar to ILP is isolated limb infusion (ILI), introduced by Thompson and colleagues from the Sydney Melanoma Unit. (1) 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. 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.
Policy:
(NOTE: For Medicare Advantage, Medicaid and FIDE-SNP, please refer to the Coverage Sections below for coverage guidance.)
1. When used as a therapeutic treatment of local recurrence of nonresectable melanoma (i.e., satellite lesions or “in transit” melanoma), isolated limb perfusion or isolated limb infusion with melphalan is considered medically necessary.
(NOTE: According to published literature, patients typically undergo one treatment with isolated limb perfusion. Some patients with incomplete responses after the first procedure may undergo a second course of treatment.)
2. When used as an adjuvant treatment of surgically treated primary malignant melanoma with no clinical evidence of disease, isolated limb perfusion or isolated limb infusion with melphalan is considered not medically necessary.
3. When used as an adjuvant treatment of surgically treated locally recurrent melanoma with no other evidence of disease, isolated limb perfusion or isolated limb infusion with melphalan is considered investigational.
4. Isolated limb perfusion or isolated limb infusion in conjunction with hyperthermia is considered investigational.
5. Isolated limb perfusion or isolated limb infusion using melphalan in conjunction with tumor necrosis factor or interferon gamma is considered investigational.
Medicare Coverage:
There is no National Coverage Determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of Local Medicare Carriers. Novitas Solutions, Inc, the Local Medicare Carrier for jurisdiction JL, has not issued a determination for this service. Therefore, Medicare Advantage Products will follow the Horizon BCBSNJ Medical Policy.
Medicaid Coverage:
For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.
FIDE-SNP:
For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.
[RATIONALE: 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. 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 one of these trials reported a highly significant improvement in overall survival, the results were so inconsistent with prior experience with ILP that researchers remain skeptical about the results of this study. The other randomized study was a small single-institution study that did not report a statistically significant improvement in overall survival. 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.
There are no randomized controlled trials 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%. 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. 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 two recurrences within fourteen months. 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. No significant difference was noted between the two 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. 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. Hyperthermia increases the regional toxicity of ILP, particularly with temperatures ≥40ºC. Although hyperthermic ILP increases response rates compared with historic controls, hyperthermia has not been demonstrated to have an effect on overall survival.
There continues to be interest in using TNF in conjunction with melphalan as the infusate. 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. 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. 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 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 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. 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.
A search of the National Cancer Institute’s Physician Data Query database returned no active phase III trials involving isolated limb perfusion and melanoma.]
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Horizon BCBSNJ Medical Policy Development Process:
This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.
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Index:
Isolated Limb Perfusion/Isolated Limb Infusion for Malignant Melanoma
Isolated Limb Infusion
Isolated Limb Perfusion for Malignant Melanoma
Chemotherapy, Isolated Regional Perfusion
Infusion, Isolated Limb
Melanoma, Malignant, of the Extremity
Perfusion, Isolated Limb
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. 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. [Available athttp://www.nccn.org/professionals/physician_gls/PDF/melanoma.pdf (last accessed on Nov 26, 2008).]
14. Olofsson R, Lindberg E, Karlsson-Parra A, et al. Melan-A specific CD8+ T lymphocytes after hyperthermic isolated limb perfusion: a pilot study in patients with in-transit metastases of malignant melanoma. Int J Hyperthermia 2013 May;29(3):234-8.
15. Olofsson R, Mattsson J, Lindner P. Long-term follow-up of 163 consecutive patients treated with isolated limb perfusion for in-transit metastases of malignant melanoma. Int J Hyperthermia 2013 Sep;29(6):551-7.
16. Squires MH 3rd, Delman KA. Current treatment of locoregional recurrence of melanoma. Curr Oncol Rep 2013 Oct;15(5):465-72.
17. Hoekstra HJ, Veerman K, van Ginkel RJ. Isolated limb perfusion for in-transit melanoma metastases: melphalan or TNF-melphalan perfusion? J Surg Oncol 2014 Mar;109(4):338-47.
18. Dossett LA, Ben-Shabat I, Olofsson Bagge R, et al. Clinical Response and Regional Toxicity Following Osilated Limb Infusion Compared with Isolated Limb Perfusion for In-Transit Melanoma. Ann Surg Oncol 2016 Jul;23(7):2330-5.
19. UpToDate. Cutaneous melanoma: Management of local recurrence. Literature review current through June 2016. Topic last updated November 9, 2015.
20. UpToDate. Cutaneous melanoma: In transit metastases. Literature review current through July 2016. Topic last updated June 28, 2016.
21. National Comprehensive Cancer Network (NCCN) Practice Guidelines in Oncology: Melanoma. Version 3.2016. 07/07/2016.
22. Tanabe KK, Tyler D. Cutaneous Melanoma: In transit metastases. In: UpToDate, Atkins MB, Berman RS, Ross ME (Eds), UpToDate, Waltham, MA. (Accessed on June 9, 2017.)
23. Tanabe KK, Tyler D. Cutaneous melanoma: Management of local recurrence. In: UpToDate, Atkins MB, Berman RS, Ross ME (Eds), UpToDate, Waltham, MA. (Accessed on June 9, 2017.)
24. Tanabe KK, Tyler D. Cutaneous Melanoma: In transit metastases. In: UpToDate, Ross ME (Eds), UpToDate, Waltham, MA. (Accessed on May 1, 2018.)
25. Tanabe KK, Tyler D. Cutaneous melanoma: Management of local recurrence. In: UpToDate, Ross ME (Eds), UpToDate, Waltham, MA. (Accessed on May 1, 2018.)
26. DeLaneyTF, Gebhardt MC, Ryan CW. Treatment of locally recurrent and unresectable, locally advanced soft tissue sarcoma of the extremities. Maki R, Pollock RE, Shah S (eds) UpToDate, Waltham, MA. (Accessed on May 1, 2019.)
27. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: Cutaneous Melanoma. V2.2019
Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)
CPT*
HCPCS
* CPT only copyright 2020 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.
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