What are the most effective treatments of satellite and in-transit metastases?
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.
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. 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.
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.
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.
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. 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%. In a retrospective review, elective lymphadenectomy had no impact on outcome.
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. 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% and treatment was well-tolerated.
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.
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%. In view of the toxicity and resources necessary for ILP, Thomson and colleagues from the Melanoma Institute of Australia introduced isolated limb infusion (ILI). 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%).
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).
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
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. Studies of combined Talimogene laherparepvec injected intra-lesionaly and PD-1 immunotherapy are currently underway.
Evidence summary and recommendations
|Topical diphenylcyclopropenone is easily administered and has limited toxicity. In up to 50% of selected patients may experience a local response.||III-2|||
|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|||
|Sentinel node biopsy provides important prognostic information and should be performed if surgical excision of in-transit recurrence is planned.||C|
|Limited disease may be treated with topical diphencyprone otherwise isolated limb infusion may be appropriate.||C|
|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|
Radiotherapy is particularly valuable for palliation of larger symptomatic lesions.
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
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.
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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