|MP 7.01.12||(Archived) Isolated Limb Perfusion/Infusion for Malignant Melanoma|
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Isolated limb perfusion (ILP) and isolated limb infusion (ILI) is a method of delivering high local levels of chemotherapy to patients with melanoma. It has been used as both therapeutic and adjuvant treatment in malignant melanoma. This technique has been studied using combination of agents as well as with hyperthermia.
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 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 thearterial 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.
Isolated Limb Perfusion (ILP)
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.
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.
Isolated limb perfusion in conjunction with hyperthermia or isolated limb perfusion using melphalan in conjunction with tumor necrosis factor or interferon gamma is considered investigational.
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.
Isolated Limb Infusion (ILI)
When used as a therapeutic treatment of local recurrence of nonresectable melanoma (i.e., satellite lesions or “in transit” melanoma), isolated limb infusion with melphalan may be considered medically necessary.
Isolated limb infusion in the treatment of melanoma is considered investigational for all other indications.
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.
Due to the reported lower morbidity with isolated limb infusion, patients may receive more than one treatment, to offer a hyperfractionated regimen.
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) 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 haveconsistently 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. A systematic evidence review, published in 2010, was based on 2,018 ILPs, with the preponderance of the evidence, 90.9%, being from observational studies. (3) This review was based on studies conducted between 1990 and 2008. The conclusions of this review are in general agreement with the policy statements; the authors comment on higher response rates in some reports using melphalan and TNF but note that two comparative studies did not find a difference in rate of CR.
As with ILP, no data from RCTs 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 was reported for 39% and partial response (PR) for 52% following a single ILI session; after 2 sessions CR was 45% and PR was 42%. Beasley and colleagues published papers on two data sets. (4,5) The first, in 2008, was a database study of 120 regionally treated melanoma patients (over the timeframe of 1995 –2007); 58 patients received ILI and 54 patients were treated with ILP; 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 (NR) was seen in 30%, 14%, and 56% of ILI recipients, respectively, versus 57%, 31%, and 12% (p <0.0001) those='those' receiving='receiving' ILP,='ILP,' ILP='ILP' recipients='recipients' did,='did,' however,='however,' have='have' number='number' toxicities:='toxicities:' 18%='18%' vs.='vs.' 32%,='32%,' respectively='respectively' (p='0.037).' (4)='(4)' second='second' study='study' published='published' 2009='2009' looked='looked' toxicity='toxicity' associated='associated' only.='only.' Patient='Patient' characteristics='characteristics' from='from' 162='162' procedures='procedures' performed='performed' at='at' 8='8' institutions='institutions' (over='(over' timeframe='timeframe' 2001–2008)='2001–2008)' were='were' compared='compared' Chi-square='Chi-square' t-statistics.='t-statistics.' Complete,='Complete,' partial,='partial,' no='no' response='response' was='was' seen='seen' 31%,='31%,' 33%,='33%,' and='and' 36%,='36%,' respectively.='respectively.' Thirty-six='Thirty-six' percent='percent' had='had' grade='grade' 3='3' or='or' greater='greater' toxicity,='toxicity,' with='with' 1='1' toxicity-related='toxicity-related' amputation.='amputation.' authors='authors' reporting='reporting' first='first' multi-institutional='multi-institutional' analysis='analysis' ILI='ILI' concluded='concluded' that='that' procedure='procedure' is='is' a='a' reasonable='reasonable' alternative='alternative' to='to' hyperthermic='hyperthermic' isolated='isolated' limb='limb' perfusion='perfusion' in='in' the='the' management='management' of='of' advanced='advanced' extremity='extremity' melanoma.='melanoma.' (5)
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 OR rate than has been reported by Beasley and colleagues (84% vs. 64%, respectively). ILI is a rare procedure with a learning curve for the technique, which can contribute to response variation. Many centers in the Beasley et al. study had completed fewer than 10 ILI procedures. (5) 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 RCT 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 RCTs 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 OS, (6) 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 OS. (7) 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 of December 2010, no new data have been published that would alter this policy statement.
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 (IFG) along with melphalan. An initial European Phase II trial that combined TNF with melphalan reported a CR rate of 90% among 28 patients, with only 2 recurrences within 14 months. (8) These results were regarded as so impressive that it was considered unethical to withhold TNF in any randomized trial. A subsequent randomized trial with some of the same group of investigators studied the use of ILP with TNF and melphalan (2-drug regimen) with and without additional IFG (3-drug regimen) in 64 patients with in-transit metastases. (9) No significant difference was noted between the two groups in terms of CR or OR rate. Continued interest in the use of TNF in conjunction with melphalan as the infusate prompted a series of studies. (10-12) 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. (13) 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 (OS). 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 CR 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.
Rossi and colleagues published a retrospective review of 53 patients who underwent treatment with melphalan for in-transit melanoma and 59 patients who also received TNF. (14) No differences were observed between the two regimens regarding toxicity, time to progression (TTP) or OS. While a higher response rate was achieved with melphalan and TNF, versus melphalan alone (60.3% vs. 41.5%, respectively), this did not translate into longer OS.
Mild hyperthermia is often used in conjunction with ILP, as in the clinical trial by Cornett and colleagues. (13) 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. (15) 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 (DFS) 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. (12) 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 IFG) is appropriate for local recurrence of unresectable melanoma. (16) 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 stated 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 investigational. Similarly, the additional benefit of IFG as part of the ILP drug regimen has not been validated and is considered investigational.
As of December 2010, no new data have been published that would alter these policy statements.
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 historic controls. Results of a large international RCT of adjuvant ILP as an adjuvant treatment in patients with high-risk primary melanoma (i.e., >1.5 mm in thickness) have been published. (17) While the incidence of local recurrence decreased in the treatment group, the OS 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. As of December 2010, no new data have been published that would alter this policy statement.
Current Clinical Trials and Guidelines
A search of the National Cancer Institute’s Physician Data Query (NCI PDQ) database returned no active Phase III trials involving isolated limb perfusion or isolated limb infusion and melanoma, as of December 2010.
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 recommendations (meaning the recommendation is based on “lower level evidence” and “nonuniform NCCN consensus” without major disagreement). (18)
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 in 2008. 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 Cornett et al., (13) the reviewer commented that no data from trials address whether hyperthermia contributes to the effect of ILP with melphalan.
- 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.
- Balch CM, Houghton AN, Sober AJ et al., eds. Cutaneous melanoma. 3rd edition. St. Louis, MO: Quality Medical Publishers, 1998. pp. 282-99.
- Moreno-Ramirez D, De la Cruz-merino L, Ferrandiz L et al. Isolated limb perfusion for malignant melanoma: systematic review on effectiveness and safety. Oncologist 2010; 15(4):416-24.
- 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):2195-205.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Rossi CR, Pasquali S, Mocellin S et al. Long-term results of melphalan-based isolated limb perfusion with or without low-dose TNF for in-transit melanoma metastases. Ann Surg Oncol 2010; 17(11):3000-7.
- 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.
- 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.
- 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.
- National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Melanoma. V.1.2011. Available online at: http://www.nccn.org/professionals/physician_gls/PDF/melanoma.pdf. Last accessed December 2010.
|CPT||36823||Insertion of arterial and venous cannula(s) for isolated extracorporeal circulation including regional chemotherapy perfusion to an extremity, with or without hyperthermia, with removal of cannula(s) and repair of arteriotomy and venotomy sites|
|ICD-9 Procedure||39.97||Other perfusion|
|99.25||Injection or infusion of cancer chemotherapeutic substance|
|ICD-9 Diagnosis||172.6||Malignant melanoma of upper limb including shoulder|
|172.7||Malignant melanoma of lower limb including hip|
|198.2||Secondary malignant neoplasm of skin|
|198.89||Secondary malignant neoplasm of other specified sites|
|HCPCS||Q0083, Q0084, Q0085||Chemotherapy administration code range (hospital use only)|
|ICD-10-CM (effective 10/1/13)||C43.0 -C43.9||Malignant melanoma of skin code range|
|C79.2||Secondary malignant neoplasm of skin|
|C79.89||Secondary malignant neoplasm of other specified sites|
|C79.9||Secondary malignant neoplasm of unspecified sites|
|D03.60 -D03.62||Malignant melanoma in situ of upper limb, including shoulder code range|
|D03.70 -D03.72||Malignant melanoma in situ of lower limb, including hip, code range|
|ICD-10-PCS (effective 10/1/13)||ICD-10-PCS codes are only used for inpatient services. There is no specific ICD-10-PCS code for this procedure.|
|3E03005||Introduction of Other Antineoplastic into Peripheral Vein, Open Approach|
|3E03305||Introduction of Other Antineoplastic into Peripheral Vein, Percutaneous Approach|
|3E05005||Introduction of Other Antineoplastic into Peripheral Artery, Open Approach|
|3E04305||Introduction of Other Antineoplastic into Central Vein, Percutaneous Approach|
|Type of Service||Surgery (for insertion of cannulas)
Medicine (for delivery of chemotherapy)
|Place of Service||Inpatient
Chemotherapy, Isolated Regional Perfusion
Isolated Limb Perfusion
Melanoma, Malignant, of the Extremity
Perfusion, Isolated Limb
|12/01/95||Add to Surgery section||New policy|
|11/01/98||Replace policy||Policy reviewed; new Indications added|
|12/15/00||Replace policy||Additional information on coding and use of tumor necrosis factor and interferon-gamma|
|10/08/02||Replace policy||Policy reviewed; policy statement unchanged. CPT codes further clarified|
|04/16/04||Replace policy||Literature review update for the period of 2002 through February 2004; policy statement unchanged|
|06/27/05||Replace policy||Literature review update for the period of 2004 through May 2005; references 9 and 11 added. The policy statement is unchanged|
|7/20/06||Replace policy||Literature review update for the period of 2005 through May 2006; no new trials found. The policy statement is unchanged|
|12/11/08||Replace policy||Literature review update for the period of 2006 through June 2008; references 12 and 13 added, clinical input reviewed. Policy statements unchanged.|
|12/10/09||Replace policy||Literature review update for the period through November 2009; reference numbers 1, 3, 4 added; reference 16 updated Policy statements rearranged; policy statement added that isolated limb perfusion with melphalan may be considered medically necessary; title changed|
|01/13/11||Replace policy||Literature review updated, reference numbers 3 and 14 added, reference 18 updated, policy statements unchanged|