What are the most effective treatments of satellite and in-transit metastases?

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Introduction

Traditionally, in-transit melanoma was defined as dermal or subcutaneous recurrence arising between the primary lesion and the draining lymph nodes and lesions within 2 cm of the scar were defined as satellite lesions although both are believed to represent arrest of tumour emboli in the dermal or subcutaneous lymphatics. In the new AJCC staging system, satellite or in-transit metastases are classified as N1,2,3c disease depending on the extent of lymph node involvement.[1]

Up to 10% of patients will develop in-transit metastases often as a first site of recurrence. The median time to presentation is approximately 12-18 months from time of definitive excision of the primary lesion.[2][3] The development of in-transit metastases is related strongly to advancing age, increasing tumour thickness, primary melanoma ulceration, mitotic rate and the presence of lymphovascular invasion as well as regional lymph node involvement (either clinically occult or apparent). Outcome is related to similar primary tumour characteristics, lymph node status and disease free interval.[2][4]

In a large Australian study of 505 patients with in-transit metastasis defined as more than 5 cm from the primary lesion, 190 had in-transit metastasis as a first presentation of recurrence. Eleven percent had a local recurrence prior to the in-transit melanoma, 42% developed regional recurrence at any time and 10% had a distant recurrence previously or concurrently with development of the in-transit metastasis.[3]

The extent of in-transit recurrence, the pace of disease and association with regional and distant spread is highly variable and makes the management of this condition difficult. The quality of evidence to guide management given the heterogenous nature of this condition is limited.

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Systematic review evidence

A systematic review was undertaken to identify evidence on effective treatments for satellite and in-transit metastatic melanoma. The evidence identified from the systematic review was low level; the highest level being level III-I. No high-level evidence was identified on which to base recommendations.

Sentinel node biopsy

Staging of patients with in-transit recurrence by sentinel node biopsy (SNB) is now incorporated in the new AJCC staging system and may be considered for patients undergoing surgical excision. Lymph node involvement detected either by clinical examination or SNB indicated poorer prognosis.[1] Five year survivals for patients with N1c (no lymph node involvement), N2c (one lymph node involved) and N3c (more than one node involved) were respectively 81%, 69% and 52%.[1] In a retrospective review, elective lymphadenectomy had no impact on outcome.[3]

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Local therapies

In addition to surgery other local therapies include laser destruction, injection of intra-lesional agents including BCG, Interleukin-2, PV-10 (rose Bengal 10%) and interferon alpha as well as a variety of topical agents including imiquamod and diphenylcyclopropenone (DCP). PV-10 followed by radiotherapy showed a complete response rate of 64% but time to in-field recurrence was short.[5] Currently only DCP is available for use in Australia. A small prospective nonrandomised study of 58 patients found a complete response rate of 22% and partial response rate of 39%[6] and treatment was well-tolerated.

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Isolated limb perfusion and isolated limb infusion

For patients with extensive in-transit recurrence, the standard of care has been isolated limb perfusion (ILP). This is a technically demanding procedure (the affected limb is isolated, maintained on a cardiac bypass machine and perfused with a heated chemotherapy solution (melphalan and actinomycin D). A complete and partial response rate of over 80% (73%-90%) was found amongst studies of ILP reporting more than 100 patients.[7][8][9][10][11][12][13][14][15][16]

Morbidity of moderate extent (Wiederbank acute limb toxicity score 3) is common (5-40%) as was severe skin and soft tissue compromise (Wiederbank acute limb toxicity score 4) 3-10%. Amputation due to severe limb toxicity occurs in 1%.[7][13][14][15][16][17] In view of the toxicity and resources necessary for ILP, Thomson and colleagues from the Melanoma Institute of Australia introduced isolated limb infusion (ILI).[18] This is a technically much easier procedure requiring far less resources and with reduced toxicity with Wiederbink acute limb toxicity scores of 3 (26- 39%) and 4 (3-13%).[7][12][19][20][21][22]

Isolated limb perfusion and ILI have not been formally compared. Non-randomised studies are not strictly comparable but indicate lower overall and complete response rates for ILI but with significantly reduced toxicity. The most mature data on ILI comes from the Melanoma Institute of Australia who reported a CR of 38% and a PR of 46%. Grouped data from other Australian centers report similar outcomes, CR 33% and PR 42%. Wiederbink acute limb toxicity Grade 3 and 4 was seen in 30% and median survival was 44 months (88 months in responders).[12][23]

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Systemic therapy

For patients with extensive and or recurrent disease, systemic therapy as for patients with disseminated disease may be appropriate. See Systemic therapy for stage 3C unresectable and stage 4 melanoma

Future developments

The role of newer strategies such as intralesionally delivered Talimogene laherparepvec a genetically modified oncolytic herpesvirus engineered to produce GM-CSF are yet to be determined in the current setting of active systemic drug therapies. The effectiveness of this strategy which leads to destruction of injected lesions as well as an immune-mediated tumoricidal effect on un-injected in-transit metastases as well as distant metastases offers the prospect of long term control.[24] Studies of combined Talimogene laherparepvec injected intra-lesionaly and PD-1 immunotherapy are currently underway.

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Evidence summary and recommendations

Evidence summary Level References
Topical diphenylcyclopropenone is easily administered and has limited toxicity. In up to 50% of selected patients may experience a local response. III-2 [6]
Isolated limb infusion (ILI) provides high rates of objective response (approximately 80%) with limited toxicity. Limb toxicity with ILI is considerably less frequent and severe than with ILP. III-2 [12]
Evidence-based recommendationQuestion mark transparent.png Grade
Sentinel node biopsy provides important prognostic information and should be performed if surgical excision of in-transit recurrence is planned.
C
Evidence-based recommendationQuestion mark transparent.png Grade
Limited disease may be treated with topical diphencyprone otherwise isolated limb infusion may be appropriate.
C
Evidence-based recommendationQuestion mark transparent.png Grade
Isolated limb infusion is preferred to isolated limb perfusion despite slightly reduced effectiveness because of less frequent and less severe toxicity and reduced resource utilisation.
C



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The role of surgery has not been evaluated prospectively but supported by limited poor quality retrospective evidence and current practice surgical excision of limited disease is appropriate. Repeat excision is appropriate for patients with limited disease.


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Radiotherapy is particularly valuable for palliation of larger symptomatic lesions.


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For patients with extensive, recurrent or progressive disease, systemic therapy (targeted and immune-therapies) is appropriate. Patients should be considered for trials. See Systemic therapy for stage 3C unresectable and stage 4 melanoma


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Sentinel node biopsy provides important prognostic information and should be considered for patients presenting with in-transit metastases who are to undergo complete surgical excision.


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Issues requiring more clinical research study

At the present time the role of systemic targeted and immune therapies for patients with melanoma is undergoing intense evaluation. The management of patients with in-transit recurrence will be directly impacted by these studies.

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References

  1. 1.0 1.1 1.2 Gershenwald JE, Scolyer RA, Hess KR, Sondak VK, Long GV, Ross MI, et al. Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin 2017 Nov;67(6):472-492 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/29028110.
  2. 2.0 2.1 Francken AB, Accortt NA, Shaw HM, Wiener M, Soong SJ, Hoekstra HJ, et al. Prognosis and determinants of outcome following locoregional or distant recurrence in patients with cutaneous melanoma. Ann Surg Oncol 2008 May;15(5):1476-84 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18196345.
  3. 3.0 3.1 3.2 Read RL, Haydu L, Saw RP, Quinn MJ, Shannon K, Spillane AJ, et al. In-transit melanoma metastases: incidence, prognosis, and the role of lymphadenectomy. Ann Surg Oncol 2015 Feb;22(2):475-81 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25256128.
  4. Stucky CC, Gray RJ, Dueck AC, Wasif N, Laman SD, Sekulic A, et al. Risk factors associated with local and in-transit recurrence of cutaneous melanoma. Am J Surg 2010 Dec;200(6):770-4; discussion 774-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21146019.
  5. Foote M, Read T, Thomas J, Wagels M, Burmeister B, Smithers BM. Results of a phase II, open-label, non-comparative study of intralesional PV-10 followed by radiotherapy for the treatment of in-transit or metastatic melanoma. J Surg Oncol 2017 Jun;115(7):891-897 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28230241.
  6. 6.0 6.1 Read T, Webber S, Tan J, Wagels M, Schaider H, Soyer HP, et al. Diphenylcyclopropenone for the treatment of cutaneous in-transit melanoma metastases - results of a prospective, non-randomized, single-centre study. J Eur Acad Dermatol Venereol 2017 Jun 19 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28626861.
  7. 7.0 7.1 7.2 Dossett LA, Ben-Shabat I, Olofsson Bagge R, Zager JS. Clinical Response and Regional Toxicity Following Isolated Limb Infusion Compared with Isolated Limb Perfusion for In-Transit Melanoma. Ann Surg Oncol 2016 Jul;23(7):2330-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26926481.
  8. Deroose JP, Grünhagen DJ, van Geel AN, de Wilt JH, Eggermont AM, Verhoef C. Long-term outcome of isolated limb perfusion with tumour necrosis factor-α for patients with melanoma in-transit metastases. Br J Surg 2011 Nov;98(11):1573-80 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21739427.
  9. Boesch CE, Meyer T, Waschke L, Merkel S, Goehl J, Hohenberger W, et al. Long-term outcome of hyperthermic isolated limb perfusion (HILP) in the treatment of locoregionally metastasised malignant melanoma of the extremities. Int J Hyperthermia 2010 Feb;26(1):16-20 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20100048.
  10. Di Filippo F, Rossi CR, Santinami M, Cavaliere F, Garinei R, Anzà M, et al. Hyperthermic isolation limb perfusion with TNFalpha in the treatment of in-transit melanoma metastasis. In Vivo 2006 Nov;20(6A):739-42 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17203758.
  11. Knorr C, Meyer T, Janssen T, Goehl J, Hohenberger W. Hyperthermic isolated limb perfusion (HILP) in malignant melanoma. Experience with 101 patients. Eur J Surg Oncol 2006 Mar;32(2):224-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16289716.
  12. 12.0 12.1 12.2 12.3 Kroon HM, Moncrieff M, Kam PC, Thompson JF. Outcomes following isolated limb infusion for melanoma. A 14-year experience. Ann Surg Oncol 2008 Nov;15(11):3003-13 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18509706.
  13. 13.0 13.1 Muilenburg DJ, Beasley GM, Thompson ZJ, Lee JH, Tyler DS, Zager JS. Burden of disease predicts response to isolated limb infusion with melphalan and actinomycin D in melanoma. Ann Surg Oncol 2015 Feb;22(2):482-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25192683.
  14. 14.0 14.1 Olofsson R, Mattsson J, Lindnér 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 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23865737.
  15. 15.0 15.1 Smith HG, Cartwright J, Wilkinson MJ, Strauss DC, Thomas JM, Hayes AJ. Isolated Limb Perfusion with Melphalan and Tumour Necrosis Factor α for In-Transit Melanoma and Soft Tissue Sarcoma. Ann Surg Oncol 2015 Sep 8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26350373.
  16. 16.0 16.1 Rossi CR, Pasquali S, Mocellin S, Vecchiato A, Campana LG, Pilati P, 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 Nov;17(11):3000-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20429035.
  17. Kroon HM, Moncrieff M, Kam PC, Thompson JF. Factors predictive of acute regional toxicity after isolated limb infusion with melphalan and actinomycin D in melanoma patients. Ann Surg Oncol 2009 May;16(5):1184-92 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19224289.
  18. Thompson JF, Kam PC, Waugh RC, Harman CR. Isolated limb infusion with cytotoxic agents: a simple alternative to isolated limb perfusion. Semin Surg Oncol 1998 Apr;14(3):238-47 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9548607.
  19. Chin-Lenn L, Temple-Oberle C, McKinnon JG. Isolated limb infusion: Efficacy, toxicity and an evolution in the management of in-transit melanoma. Plast Surg (Oakv) 2015;23(1):25-30 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25821769.
  20. Beasley GM, Petersen RP, Yoo J, McMahon N, Aloia T, Petros W, 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 Aug;15(8):2195-205 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18528730.
  21. Lidsky ME, Turley RS, Beasley GM, Sharma K, Tyler DS. Predicting disease progression after regional therapy for in-transit melanoma. JAMA Surg 2013 Jun;148(6):493-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23558401.
  22. Wong J, Chen YA, Fisher KJ, Zager JS. Isolated limb infusion in a series of over 100 infusions: a single-center experience. Ann Surg Oncol 2013 Apr;20(4):1121-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23456376.
  23. Kroon HM, Coventry BJ, Giles MH, Henderson MA, Speakman D, Wall M, et al. Australian Multicenter Study of Isolated Limb Infusion for Melanoma. Ann Surg Oncol 2016 Apr;23(4):1096-103 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26581203.
  24. Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, et al. Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. J Clin Oncol 2015 Sep 1;33(25):2780-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26014293.

Appendices


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