Pending Policies - Surgery


Isolated Limb Perfusion/Infusion for Malignant Melanoma

Number:SUR701.010

Effective Date:01-01-2018

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

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 for melanoma in patients with:

Unresectable Stage III disease with clinical satellite or in-transit metastases; or

Unresectable local, satellite and/or intransit recurrence.

ILP with melphalan, with or without hyperthermia OR ILI with melphalan, with or without hyperthermia, is considered experimental, investigational and/or unproven when used for the treatment of melanoma in patients not meeting the above noted indications.

Description:

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 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. The adjuvant setting can be further broken down into its use after initial resection of primary melanoma, considered 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.

Rationale:

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/or 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/or 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)

2012 Update

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)

2015 Update

A search of peer reviewed literature through January 2015 was performed. No additional information was identified that would change the coverage position of this medical policy.

2017 Update

A search of Medline and the NCCN Guidelines and Compendium was conducted through June 2017.

The NCCN Guidelines Version 1.2017 for Melanoma notes that in general, cutaneous melanomas are categorized as follows: localized disease with no evidence of metastases (stage I-II), regional disease (stage III), and distant metastatic disease (stage IV). (19)

The NCCN Compendium and NCCN Guidelines both note Melphalan as a 2A category recommendation for isolated limb perfusion or infusion as treatment of unresectable stage III disease with clinical satellite or in-transit metastases; or unresectable local, satellite and/or in-transit recurrence. (19, 20)

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

36823, 77600, 77605

HCPCS Codes

J9245

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. Thompson JF, Kam PC, Waugh RC, et al. Isolated limb infusion with cytotoxic agents: a simple alternative to isolated limb perfusion. Semin Surg Oncol 1998; 14(3):238-47. PMID 9548607

2. Balch CM, Houghton AN, Sober AJ, et al., eds. Cutaneous melanoma. 3rd edition. St. Louis, MO: Quality Medical Publishers, 1998. pp. 282-99.

3. 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 2008; 15(8):2195-2205. PMID 18528730

4. Beasley GM, Caudle A, Petersen RP, et al. A multi-institutional experience of isolated limb infusion: defining response and toxicity. J Am Coll Surg 2009; 208(5):706-15. PMID 19476821

5. 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. PMID 3276384

6. 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. PMID 1960549

7. 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. PMID 1727926

8. 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. PMID 10596916

9. 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. PMID 11417986

10. 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. PMID 11986187

11. 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. PMID 14761920

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. PMID 16943537

13. 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. PMID 12883366

14. 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. PMID 15313738

15. 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.

16. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Melanoma. V.2.2009. Available at <https://www.nccn.org> (accessed November 2009).

17. Isolated Limb Perfusion/Infusion for Malignant Melanoma-Archived. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2009 December) Surgery 7.01.12

18. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Melanoma. V2.2015. Available at <https://www.nccn.org> (accessed January 26, 2015).

19. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Melanoma. V1.2017. Available at <https://www.nccn.org> (accessed June 27, 2017).

20. National Comprehensive Cancer Network – Melphalan; Melphalan hydrochloride (2017) National Comprehensive Cancer Network Drugs & Biologics Compendium. Available at <https://www.nccn.org> (accessed June 27,2017).

Policy History:

DateReason
1/1/2018 Document updated with literature review. Coverage has changed to the following: 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 for Melanoma in patients with: Unresectable Stage III disease with clinical satellite or in-transit metastases or Unresectable local, satellite and/or intransit recurrence. ILP with melphalan, with or without hyperthermia OR ILI with melphalan, with or without hyperthermia, is considered experimental, investigational and/or unproven when used for the treatment of Melanoma in patients not meeting the above noted indications.
7/15/2016 Reviewed. No changes.
4/1/2015 Document updated with literature review. No change in coverage.
9/1/2012 Document updated with literature review. The following changes were made: Coverage statements for ILP and ILI combined to note: ILP/ILI with melphalan (with or without hyperthermia) may be considered medically necessary when criteria are met. The following has been removed: ILI in the treatment of melanoma is considered experimental, investigational and unproven for all other indications.
9/15/2010 Document updated with literature review. The following changes were made: Isolated limb infusion (ILI) with melphalan may be considered medically necessary for local recurrence of non-resectable melanoma; all other uses of ILI for melanoma are investigational; title changed.
7/1/2009 Policy updated with literature review. No change in coverage.
9/15/2007 Revised, Updated Entire Document
8/1/2005 Revised, Updated Entire Document
11/1/2000 Revised, Updated Entire Document
1/1/2000 Revised, Updated Entire Document
5/1/1999 Revised, Updated Entire Document
3/1/1998 Revised, Updated Entire Document
5/1/1996 Revised, Updated Entire Document
10/1/1992 Revised, Updated Entire Document
5/1/1990 New Medical Document

Archived Document(s):

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