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Cutaneous melanoma: In-transit metastases

Cutaneous melanoma: In-transit metastases
Literature review current through: Jan 2024.
This topic last updated: Nov 01, 2022.

INTRODUCTION — For patients with primary cutaneous melanoma, the term "locoregional metastases" includes local recurrences, in-transit and satellite metastases, and regional lymph node metastases.

The clinical presentation, evaluation, and management of patients with in-transit metastases will be reviewed here. Local recurrences and nodal metastases are discussed separately. (See "Cutaneous melanoma: Management of local recurrence" and "Evaluation and management of regional nodes in primary cutaneous melanoma".)

DEFINITION — In-transit metastases are located within regional dermal and subdermal lymphatics prior to reaching the regional lymph nodes. The American Joint Committee on Cancer (AJCC) defines in-transit metastases as any skin or subcutaneous metastases that are more than 2 cm from the primary lesion but are not beyond the regional nodal basin [1]. Lesions occurring within 2 cm of the primary tumor are classified as satellite metastases. The distinction between satellite lesions and in-transit metastases is not necessary from a clinical perspective since both represent a manifestation of intralymphatic disease. Satellite lesions and in-transit metastases are grouped together and considered intralymphatic in the AJCC staging system [2]. In the eighth (2017) AJCC tumor, node, metastasis (TNM) staging system, non-nodal regional disease is stratified by category according to the number of tumor-involved lymph nodes (table 1A and table 1B). (See "Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma".)

In-transit metastases are differentiated from satellite lesions, which are skin or subcutaneous lesions within 2 cm of the primary tumor that are considered intralymphatic extensions of the primary mass. Despite this distinction, the tumor biology associated with satellite and in-transit metastases is similar, and they are not considered as distinct entities for treatment or prognosis [3,4].

CLINICAL PRESENTATION — Melanoma in-transit metastases typically appear as erythematous nodules of variable size that may or may not be pigmented. Occasionally, the lesions are flat rather than nodular depending on their location in the epidermis, dermis, or subcutaneous tissue.

Although in-transit metastases typically are located between the primary site and the regional nodes, they may extend in a direction opposite to that of the closest regional nodal basin in patients with extensive disease, particularly in the lower extremities. This manifestation presumably reflects tumor blockage of lymphatic channels and altered patterns of lymphatic flow. Uncontrolled tumor growth can result in coalescence of lesions and tumor ulceration.

For patients who present with in-transit metastases, a careful clinical and imaging assessment is necessary to determine whether distant metastases are also present. (See "Imaging studies in melanoma", section on 'Approach to patient imaging based on disease site'.)

INCIDENCE AND INFLUENCE OF NODE DISSECTION — An estimate of the incidence of in-transit metastases comes from a study of 11,614 patients treated at the Melanoma Institute Australia between 1994 and 2009 [5]. Overall, in this series, 505 patients (4 percent) developed in-transit metastases.

In-transit metastases were predominantly associated with thicker primary tumors; the incidence was 0.4 percent in those with primary tumors <1 mm thick and 7.8 percent for those with primary tumors ≥1 mm thick.

In-transit metastases were also associated with sentinel lymph node metastases; the incidence was 21.6 percent in those with a positive sentinel lymph node and 4.7 percent in those with a negative sentinel lymph node.

The median time to the development of in-transit metastases after the diagnosis of the primary tumor was 18 months, and the median survival following the diagnosis of in-transit metastases was 20 months.

Other factors reported to be associated with an increased risk of subsequent in-transit metastases include the presence of ulceration in the primary tumor, location of the primary on the lower extremity, lymphovascular invasion, and positive regional lymph nodes at presentation.

Multiple studies have provided evidence that lymphatic disruption from surgical management of the regional lymphatics is not an independent risk factor for in-transit metastases or local recurrences [6-9], although a possible risk had been suggested by earlier observational data [10,11]:

In a retrospective series of 4412 patients with stage I or II melanoma, the incidence of in-transit metastases was significantly higher in patients undergoing a wide local excision (WLE) plus elective lymph node dissection (ELND; 6.6 versus 3.4 and 3.6 percent for WLE without and with sentinel lymph node [SLN] biopsy, respectively) [8]. However, the higher rate of such metastases in patients undergoing ELND was explained by differences in the patient characteristics, with those undergoing ELND having more high-risk features at presentation.

In a study of 1395 patients with extremity melanoma who underwent lymphatic mapping and SLN biopsy, 6.5 percent developed in-transit recurrence at a mean follow-up of 3.5 years [6]. In 71 percent of these patients, the in-transit disease was the only site of recurrence.

The Multicenter Selective Lymphadenectomy Trial (MSLT-I) randomly assigned patients with intermediate thickness melanoma to observation, or lymphatic mapping and SLN biopsy [9]. There was no difference in the rate of local recurrence or in-transit metastases. (See "Evaluation and management of regional nodes in primary cutaneous melanoma".)

TREATMENT

General approach — The approach to treatment takes into account the anatomic site and extent of locoregional disease, the overall condition of the patient, the presence or absence of disseminated metastases, and prior therapies.

While there may be debate as to what defines appropriately resectable disease, the presence of three or more lesions or resection of single lesions in which the skin cannot be closed primarily after removal should give the surgeon pause to evaluate alternative treatments as initial therapy. Given the significant advances and effectiveness of systemic therapy that has generally less toxicity than limb infusion or perfusion, the role of regional therapies is evolving. With the development of effective systemic treatments, regional treatments (especially limb perfusion and infusion) are thought about more as adjuncts to systemic therapy to improve locoregional control and/or to alter the regional tumor microenvironment and thus augment systemic immunotherapy treatment strategies.

Surgery (resection, limb perfusion, limb infusion) has a role for salvage therapy for nonresponding metastatic lesions when there is evidence of response to systemic therapy elsewhere in the body. The mechanism of this is not clear but may involve mutations within the tumor that make it resistant to targeted therapy, or antigenic variation making it resistant to an immune response that is effective elsewhere in the body [12,13].

For patients with no distant metastatic disease, resection of single or multiple in-transit metastases is the treatment of choice when complete resection can be achieved with an acceptable morbidity. (See 'Surgery' below.)

Postoperatively, most of these patients should be evaluated for adjuvant systemic therapy in the form of immunotherapy or targeted BRAF/MEK inhibitors. (See 'Adjuvant systemic therapy' below and "Adjuvant and neoadjuvant therapy for cutaneous melanoma".)

For patients with no distant metastatic disease and unresectable or recurrent in-transit disease, multidisciplinary discussion is indicated to evaluate optimal sequencing of systemic therapy versus regional chemotherapy (eg, isolated limb perfusion [ILP] or isolated limb infusion [ILI]) (figure 1) or intralesional treatment (eg, talimogene laherparepvec [T-VEC]). Increasingly, a systemic neoadjuvant approach is being applied to these patients based on data suggesting high response rates with both targeted therapies [14] as well as immunotherapy [15,16]. (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma".)

For patients in whom surgical resection is not feasible, regional chemotherapy with either ILP or ILI using melphalan is a potential option if there is access to a center with adequate expertise in this technique. Data suggest that combination of regional therapy followed by checkpoint inhibitor immunotherapy using ipilimumab has better regional and systemic disease control than regional chemotherapy alone [17,18]. (See 'Regional chemotherapy' below.)

For patients with unresectable but limited burden of visceral metastases in whom a component of their disease includes injectable cutaneous, dermal, subcutaneous, or nodal metastases, T-VEC is another treatment option. T-VEC is most effective for small-volume, less than 3 cm subcutaneous lesions. (See 'Intralesional therapy (T-VEC)' below.)

For patients who are ineligible for surgery, regional chemotherapy, and intralesional therapy, radiation therapy (RT) may provide palliative benefit. (See 'Radiation therapy' below.)

For patients with distant metastases, systemic treatment options should be offered as initial therapy, although surgery or RT may be indicated in rare instances to prevent the morbidity associated with uncontrolled locoregional disease. (See 'Systemic therapy' below and "Systemic treatment of metastatic melanoma lacking a BRAF mutation" and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations".)

Evaluation — Patients with one or more in-transit metastases should undergo a careful evaluation for distant sites of recurrence, including a careful history and physical examination and appropriate imaging studies. (See "Imaging studies in melanoma", section on 'Approach to patient imaging based on disease site'.)

Lymphatic mapping and sentinel lymph node (SLN) biopsy can be performed, even in patients who had a previous SLN biopsy, and can be useful in determining the extent of surgery. The technique, while similar to that described for patients with primary melanoma, is not standardized (eg, how many in-transit metastases to inject, whether or not to inject the site of the primary lesion, in-transit metastases, or both). When SLN biopsy is performed, the most popular technique is to inject radiocolloid and/or blue dye around the most proximal in-transit lesion [19]. (See "Cutaneous melanoma: Management of local recurrence", section on 'Lymphatic mapping and SLNB'.)

The utility of SLN biopsy in patients with in-transit disease has not been clearly delineated. How additional staging information from this procedure might influence patient management or eligibility for clinical trials should be discussed in a multidisciplinary tumor board that has expertise in melanoma management. SLN biopsy may have its biggest role in patients with small volume in-transit disease in whom positron emission tomography (PET)/computed tomography (CT) shows no metastatic disease and where the potential treatment options range from simple excision through regional treatment to systemic therapy.

The staging work-up of patients with in-transit melanoma is discussed in detail separately. (See "Staging work-up and surveillance of cutaneous melanoma", section on 'Clinically evident lymph nodes or in-transit/satellite metastases'.)

Surgery

Indications for surgery — In patients without distant metastases, resection of single or multiple in-transit metastases is the treatment of choice when technically feasible with an acceptable level of morbidity. While there may be debate as to what defines technically resectable, the presence of three or more lesions or resection of single lesions in which the skin cannot be closed primarily after removal should give the surgeon pause to evaluate alternative treatments as initial therapy.

For patients in whom a sentinel lymph node biopsy demonstrated metastatic disease, completion lymph node dissection does not improve survival based on randomized trial data [20-22]. Patients being evaluated for nodal dissection should be discussed at a multidisciplinary tumor board in order to contemplate the need for additional prognostic information; clinical trial eligibility; ability of the patient to participate in close follow-up of the regional nodal basin; and local basin tumor control. The approach to nodal dissection in patients with advanced cutaneous melanoma is discussed separately. (See "Evaluation and management of regional nodes in primary cutaneous melanoma".)

Although the majority of patients will develop disseminated disease, a subset of those without distant metastases enjoy long-term relapse-free survival following surgery with a curative intent. As an example, in a study of 648 patients with locally recurrent melanoma at first relapse who underwent complete surgical resection, 124 (19 percent) had not relapsed at a median follow-up of eight years [23]. The incidence rates for subsequent local recurrence, lymph node disease, and systemic metastases were 45, 34, and 17 percent, respectively. Truncal primary tumor location and shorter disease-free intervals were associated with poorer outcomes following locoregional disease recurrence.

Even if distant metastases are present, locoregional disease control is an important issue for quality of life because of pain and wound complications from ulcerating tumors. In some cases, surgery may be indicated to reduce or delay the morbidity (bleeding, ulceration, pain) associated with progression of in-transit disease.

Sound clinical judgment is needed to assess the feasibility of resection for in-transit metastases. Most patients who undergo resection will relapse, usually with additional in-transit metastases. In most patients, the morbidity associated with excision of a few in-transit metastases every 6 to 18 months is acceptable. However, an increased frequency of in-transit melanoma relapses or a greater number of in-transit nodules suggests that alternative regional or systemic treatments should be evaluated.

The surgical principles for treating in-transit lesions differ from those for a primary melanoma. A histologically negative margin is adequate, and the wider margins that are used to treat primary melanomas are not indicated. Depending upon the size of the metastases and the proximity to the original excision, the surgical defect may not be amenable to primary closure and may require skin grafting. (See "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites".)

Positive resection margins — For patients with microscopically, but not grossly, positive margins following resection of in-transit metastases, we recommend reresection to clear the surgical margins only in those with the most favorable tumor biology. Observation followed by resection of any recurrence that subsequently develops is an appropriate alternative, especially if patients are being evaluated for adjuvant systemic therapy. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation" and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations".)

There are no data that directly compare outcomes following reresection with observation for management of histologically positive margins. The benefit of reresection to achieve negative margins must be balanced against the morbidity of the procedure. Since the vast majority of these patients harbor additional occult metastases in regional lymphatic channels, the value of reresection to clear surgical margins is very limited.

Furthermore, although the goal of resection is to achieve histologically negative margins, microscopically positive margins are sometimes identified in the resection specimen. This does not necessarily mean that melanoma cells were left behind in the excision bed. Subcutaneous fat is loose tissue that is easily brushed aside during the process of inking the specimen, and the ink may have been inadvertently applied to the pseudocapsule of a completely excised in-transit metastases.

Systemic therapy — Data suggest that systemic therapies used in patients with metastatic melanoma, such as checkpoint inhibitor immunotherapy or targeted therapies against the BRAF V600 mutation, are effective as initial therapy in patients with in-transit melanoma who are not candidates for surgical resection [24,25]. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation" and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations" and "Adjuvant and neoadjuvant therapy for cutaneous melanoma".)

However, the data regarding the efficacy of systemic therapy specifically for in-transit melanoma and no systemic metastases are more limited. As an example, in a retrospective study of 54 patients with in-transit melanoma only and no distant metastases treated with immunotherapy (single-agent or combination therapy), the overall response rate was 54 percent and two-year PFS was 39 percent, respectively. Locoregional progression was seen in 14 of 25 patients (56 percent) [26].

Regional chemotherapy

Indications for regional chemotherapy — Regional chemotherapy using isolated limb perfusion (ILP) or isolated limb infusion (ILI) is reserved for patients with unresectable recurrences who are not candidates for systemic therapies or have progressed on systemic therapies. As available systemic therapy options have increased and intralesional injectable treatments have received regulatory approval from the US Food and Drug Administration (FDA), the number of regional chemotherapy procedures (ILP or ILI) performed has decreased markedly in the United States. There are no randomized trials that examine regional chemotherapy delivered using hyperthermic ILP as compared to ILI, or comparing either regional chemotherapy treatment to surgical excision of in-transit metastases alone or to newer systemic therapies with or without surgical excision. Some unresectable recurrences may be converted to resectable following a response to ILP or ILI therapy.

Options and technique — Regional chemotherapy using ILP or ILI techniques allows the delivery of relatively high concentrations of cytotoxic agents to an involved extremity while avoiding systemic toxicity. Hyperthermic ILP is effective, but it is time and resource consuming, as well as toxic [27]. ILI was developed as a simpler and less toxic technique to achieve high regional drug concentrations.

Both techniques are still in use, and institutional preferences for one technique over the other are generally related to the preferences of the melanoma team and surgeon experience with each of the procedures. As systemic therapies have improved, the number of patients with regionally confined in-transit disease of the extremities that go straight to regional chemotherapy treatment has decreased markedly. Given the variety of options now available for these patients, optimal sequencing of treatments is complex and not uniformly agreed upon. Data suggest that combination of regional therapy followed by checkpoint blockade immunotherapy has better regional and systemic disease control than regional chemotherapy alone [17,18]. Multidisciplinary discussion of these patients is strongly encouraged.

Melphalan is the standard drug for regional chemotherapy because of its rapid uptake by cells and because its mechanism of action is independent of the cell cycle [28-32]. Other agents that have been utilized include dactinomycin, tumor necrosis factor (TNF), cisplatin, dacarbazine, and temozolomide, although no advantage from combining any of these agents with melphalan has been demonstrated.

Responses to regional chemotherapy with or without hyperthermia occur gradually, and maximal tumor regression is usually present within three months (picture 1). Patients who have a partial response at reassessment can undergo resection, if the disease is deemed resectable, or undergo a repeat regional chemotherapy treatment. Options for patients who progress include alternative regional chemotherapy regimens or systemic therapy.

Isolated limb perfusion — ILP surgically separates the vascular inflow and outflow of the affected extremity from that of the remainder of the body. Thus, high concentrations of drugs are circulated locally without exposing the rest of the body to the same level of toxicity. By excluding the liver and kidney from the perfusion circuit, drug metabolism is minimized, thus leading to sustained high concentrations of drug in the perfused limb [33].

Vascular isolation of the extremity is needed to avoid leakage of perfusate into the systemic circulation and of systemic blood into the perfusion circuit. A tourniquet is applied around the root of the extremity to occlude superficial veins that could communicate between the limb circuit and the remainder of the body.

The isolated extremity is usually subjected to mild hyperthermia (≤40°C), which produces vasodilatation that is thought to improve antitumor effect while not subjecting the entire body to the risks of hyperthermia. Hyperthermia increases the regional toxicity of ILP, particularly with temperatures ≥40°C [34]. Although hyperthermic ILP increases response rates compared with historic controls, hyperthermia has not been demonstrated to have an effect on overall survival.

ILP of the lower extremities is most commonly performed via cannulation of the external iliac vessels; the axillary vessels are used in the arm. However, ILP can be performed via the femoral or popliteal vessels in the lower extremity, and via the brachial vessels in the arm in certain clinical situations, such as a redo perfusion or in an individual who has had a previous pelvic or axillary lymph node dissection. The vessels are cannulated and connected to the inflow and outflow lines of an extracorporeal bypass circuit identical to that used in cardiac surgery.

The dose of melphalan is generally based upon the volume of the extremity (10 mg/L limb volume for lower extremity and 13 mg/L limb volume for upper extremity) [35]. The optimal duration of perfusion has not been studied critically, but most surgeons perfuse for 60 minutes.

Isolated limb infusion — Normothermic ILI has been developed as a more convenient and less invasive alternative for regional chemotherapy [36-38]. With ILI, the artery and vein of an extremity are accessed percutaneously using high-flow catheters, and a pneumatic tourniquet is used proximally to isolate the extremity (figure 1).

ILI differs from ILP in that ILI circulates blood in an isolated extremity at a much slower rate than ILP and for only 30 minutes, and hyperthermia is not achieved. During ILI, the extremity is hypoxic, which leads to marked acidosis. In contrast, with hyperthermic ILP, the pump oxygenator maintains the oxygenation and normal acid/base status of the extremity.

Outcomes — There are no randomized clinical trials comparing ILP with ILI. The ILP procedure is more complicated and has been associated with more toxicity.

The outcomes with each approach are illustrated by the following:

ILP – In a multicenter trial, 133 patients with melanoma in-transit metastases were treated with standard hyperthermic ILP and randomly assigned to treatment using either melphalan or melphalan plus TNF-alpha [39]. The procedure was successfully completed in 124 cases (93 percent). There was no significant difference in efficacy with the two different treatment regimens. Overall, 76 patients (57 percent of the total study population) had a response, and 29 (22 percent) had a complete response. There were two amputations related to treatment but no treatment-related deaths.

ILI – In the largest reported experience, the outcomes in 316 melanoma patients treated with ILI using melphalan (with or without dactinomycin) were analyzed [40]. The overall response rate was 75 percent, and the complete response rate was 33 percent. There were no treatment-related amputations. Similar results were observed in a combined report of 157 patients who were treated with ILI from eight centers in the United States [41]. Dactinomycin was added to the melphalan regimen in 93 percent of infusions. The overall response rate was 64 percent, including 31 percent complete responses, in the 128 evaluable patients. Grade 3 or greater toxicity was observed in 36 percent of cases, and one patient required an amputation because of toxicity.

ILI versus ILP – A combined analysis of the ILI experience from the Sydney Melanoma Unit, Duke, and the United States multicenter study compared outcomes with previously published reports using ILP. The overall response rate was higher with ILP than with ILI (79 percent in 294 patients versus 64 percent in 313 patients) [41]. The rate of complete response was 50 percent with ILP versus 33 percent with ILI. The overall incidence of grade 3 or greater toxicity was similar (29 versus 33 percent), but ILP resulted in more grade 5 toxicity (2.0 versus 0.3 percent). A similar difference in response rate and an absence of difference in overall survival have been observed in another retrospective analysis [42].

Special populations

Regional chemotherapy followed by adjuvant systemic therapy — Patients who achieve a complete response with regional chemotherapy alone may be evaluated for adjuvant systemic therapy. There is significant interest in determining whether ILI generates an immune response that can be augmented by systemic immunotherapy to help eliminate metastatic disease outside the field of regional treatment. Data suggest that combination of regional therapy followed by checkpoint inhibitor immunotherapy has better regional and systemic disease control than regional chemotherapy alone [17,18]. (See 'Adjuvant systemic therapy' below.)

Is there a role for regional chemotherapy after resection of in-transit recurrences? — Although patients who undergo resection for in-transit recurrent melanoma in the extremity are at high risk for additional metastases, adjuvant regional chemotherapy is not routinely utilized after resection of an initial in-transit recurrence.

A Swedish trial randomly assigned 69 patients with resected melanoma recurrences to excision alone or surgery followed by hyperthermic ILP using melphalan [43]. ILP decreased the incidence of local recurrences (70 versus 83 percent without ILP) and was associated with a better three-year disease-free survival (33 versus 17 percent). However, overall survival was not significantly improved (55 versus 45 percent).

Although we may evaluate the use of adjuvant regional chemotherapy for patients with multiple recurrences who have had their most recent recurrence completely resected and continue to have negative regional lymph nodes, our preference is to limit regional therapies to those patients in whom in-transit metastases cannot be fully resected.

Is there a role for regional chemotherapy in high-risk primary melanoma? — Regional chemotherapy is not recommended for patients in the adjuvant setting after resection of high-risk primary tumors.

Progression after regional chemotherapy treatment — Approximately 65 to 85 percent of patients who have a complete response to ILP or ILI will develop a regional recurrence [17]. The use of systemic therapy should be evaluated if disease is not amenable to surgical excision or repeat regional chemotherapy, or if distant metastases are present. (See "Overview of the management of advanced cutaneous melanoma".)

Although there are only limited data from patients in this setting, one retrospective study observed complete tumor regression in 6 of 18 patients treated with ipilimumab immunotherapy [17]. There were no complete responses in the 21 patients who were treated with interleukin-2 (IL-2) following regional chemotherapy.

Intralesional therapy (T-VEC)

Resectable disease (neoadjuvant therapy) — The use of talimogene laherparepvec (T-VEC) as neoadjuvant therapy followed by surgical resection in patients with locoregionally advanced melanoma is discussed separately. (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma", section on 'Other agents'.)

Unresectable disease with limited visceral metastases — For patients with unresectable but limited burden of visceral metastases in whom a component of their disease includes injectable cutaneous, dermal, subcutaneous, or nodal metastases, T-VEC is another treatment option. T-VEC is most effective for carefully selected patients with small-volume, less than 3 cm subcutaneous lesions. Intralesional injection of T-VEC is also FDA approved to treat dermal and epidermal melanoma metastases.

In a phase III trial (OPTiM), 436 patients with unresectable or metastatic melanoma were randomized to intralesional T-VEC versus systemic granulocyte-macrophage colony-stimulating factor (GM-CSF) [44-46]. At a median follow-up of approximately four years, compared with GM-CSF, T-VEC increased durable response rates (19 versus 1 percent) but had similar overall survival rate (median 23 versus 19 months). There was a bystander effect in the T-VEC arm where some uninjected lesions did regress both subcutaneously and viscerally [44,45].

Metastatic disease — The use of T-VEC in patients with metastatic disease is discussed separately. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Investigational agents'.)

Radiation therapy — RT is used infrequently for in-transit metastases and is limited to situations in which disease is too extensive for surgical excision and regional chemotherapy or intralesional therapies are either not possible or ineffective. RT may provide palliative benefit and, occasionally, prolonged regional control. (See "Radiation therapy in the management of melanoma".)

Adjuvant systemic therapy — While satellite/in-transit metastases and nodal metastases both appear to be evidence of micrometastasis through the lymphatics that drain the primary melanoma, there may be important molecular differences that direct the cells toward the skin versus the nodes. There is increasing evidence that the patient population with in-transit disease benefits from systemic adjuvant therapy [17,18] and potentially even neoadjuvant therapies [47]. Further details are discussed separately. (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma".)

Randomized clinical trials of adjuvant therapy that included patients who are rendered disease free following treatment of in-transit metastases, and are clinically or pathologically node negative showed relapse-free survival benefit with nivolumab compared to ipilimumab. Therefore, the indications for adjuvant therapy are similar to those in patients with lymph node involvement. (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma", section on 'Factors that influence therapy'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Melanoma screening, prevention, diagnosis, and management".)

SUMMARY AND RECOMMENDATIONS

Definition – Melanoma satellite lesions and in-transit metastases are manifestations of lymphatic tumor spread. Because their tumor biology and prognosis are similar, they are grouped together in the tumor node metastasis (TNM) staging system (table 1A-B). (See 'Definition' above and 'Clinical presentation' above.)

Initial evaluation – For patients with in-transit metastases, careful assessment is necessary to determine whether disseminated disease is present and the extent of such disease. (See 'Evaluation' above and "Staging work-up and surveillance of cutaneous melanoma", section on 'Clinically evident lymph nodes or in-transit/satellite metastases'.)

Multidisciplinary evaluation – Aggressive treatment may be associated with prolonged survival when disease is limited to the extremity and there is no evidence of other metastases. Management of in-transit disease requires a multidisciplinary approach that evaluates each patient's unique situation and access to surgical expertise for regional treatment options as well as access to medical oncology expertise for systemic therapy options. Clinical trial participation should be encouraged in this group of patients when possible. (See 'General approach' above.)

Resectable disease – For patients with a limited number of resectable in-transit metastases but without other evidence of disseminated disease, we recommend surgical resection of all disease with curative intent (Grade 1B). (See 'Surgery' above.)

Patients who have undergone a complete resection of all disease should be evaluated for adjuvant systemic therapy. (See 'Adjuvant systemic therapy' above and "Adjuvant and neoadjuvant therapy for cutaneous melanoma", section on 'Factors that influence therapy'.)

Unresectable or recurrent disease – For patients with unresectable or recurrent in-transit disease of the extremity and with no systemic disease, we suggest multidisciplinary discussion to determine optimal sequencing of systemic therapy, versus isolated limb perfusion (ILP) or isolated limb infusion (ILI), versus intralesional treatment with talimogene laherparepvec (T-VEC) (Grade 2C). (See 'Regional chemotherapy' above and 'Intralesional therapy (T-VEC)' above.)

In-transit and systemic metastases – For patients with metastatic disease and a limited number of in-transit metastases, we suggest systemic therapy rather than regional therapeutics (Grade 2B). Regional therapeutic treatments (surgery, regional chemotherapy, or intralesional therapy) are generally reserved for palliation or treatment consolidation. (See 'Systemic therapy' above.)

  1. Melanoma of the skin. In: American Joint Committee on Cancer Staging Manual, 7th ed, Edge SB, Byrd DR, Compton CC, et al (Eds), Springer, 2010. p.325.
  2. Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma of the Skin. In: AJCC Cancer Staging Manual: Eighth Edition, Amin MB (Ed), American Joint Committee on Cancer, Chicago 2017. p.563.
  3. Balch CM, Buzaid AC, Soong SJ, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 2001; 19:3635.
  4. Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 2001; 19:3622.
  5. Read RL, Haydu L, Saw RP, et al. In-transit melanoma metastases: incidence, prognosis, and the role of lymphadenectomy. Ann Surg Oncol 2015; 22:475.
  6. Pawlik TM, Ross MI, Johnson MM, et al. Predictors and natural history of in-transit melanoma after sentinel lymphadenectomy. Ann Surg Oncol 2005; 12:587.
  7. Kretschmer L, Beckmann I, Thoms KM, et al. Factors predicting the risk of in-transit recurrence after sentinel lymphonodectomy in patients with cutaneous malignant melanoma. Ann Surg Oncol 2006; 13:1105.
  8. Kang JC, Wanek LA, Essner R, et al. Sentinel lymphadenectomy does not increase the incidence of in-transit metastases in primary melanoma. J Clin Oncol 2005; 23:4764.
  9. Morton DL, Thompson JF, Cochran AJ, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med 2014; 370:599.
  10. Thomas JM, Clark MA. Selective lymphadenectomy in sentinel node-positive patients may increase the risk of local/in-transit recurrence in malignant melanoma. Eur J Surg Oncol 2004; 30:686.
  11. Estourgie SH, Nieweg OE, Kroon BB. High incidence of in-transit metastases after sentinel node biopsy in patients with melanoma. Br J Surg 2004; 91:1370.
  12. Nelson DW, Fischer TD, Graff-Baker AN, et al. Impact of Effective Systemic Therapy on Metastasectomy in Stage IV Melanoma: A Matched-Pair Analysis. Ann Surg Oncol 2019; 26:4610.
  13. Bello DM, Panageas KS, Hollmann T, et al. Survival Outcomes After Metastasectomy in Melanoma Patients Categorized by Response to Checkpoint Blockade. Ann Surg Oncol 2020; 27:1180.
  14. Amaria RN, Prieto PA, Tetzlaff MT, et al. Neoadjuvant plus adjuvant dabrafenib and trametinib versus standard of care in patients with high-risk, surgically resectable melanoma: a single-centre, open-label, randomised, phase 2 trial. Lancet Oncol 2018; 19:181.
  15. Song Y, Straker RJ 3rd, Xu X, et al. Neoadjuvant Versus Adjuvant Immune Checkpoint Blockade in the Treatment of Clinical Stage III Melanoma. Ann Surg Oncol 2020; 27:2915.
  16. Amaria RN, Reddy SM, Tawbi HA, et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat Med 2018; 24:1649.
  17. Jiang BS, Beasley GM, Speicher PJ, et al. Immunotherapy following regional chemotherapy treatment of advanced extremity melanoma. Ann Surg Oncol 2014; 21:2525.
  18. Ariyan CE, Brady MS, Siegelbaum RH, et al. Robust Antitumor Responses Result from Local Chemotherapy and CTLA-4 Blockade. Cancer Immunol Res 2018; 6:189.
  19. Beasley GM, Speicher P, Sharma K, et al. Efficacy of repeat sentinel lymph node biopsy in patients who develop recurrent melanoma. J Am Coll Surg 2014; 218:686.
  20. Faries MB, Thompson JF, Cochran AJ, et al. Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. N Engl J Med 2017; 376:2211.
  21. Leiter U, Stadler R, Mauch C, et al. Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial. Lancet Oncol 2016; 17:757.
  22. Leiter U, Stadler R, Mauch C, et al. Final Analysis of DeCOG-SLT Trial: No Survival Benefit for Complete Lymph Node Dissection in Patients With Melanoma With Positive Sentinel Node. J Clin Oncol 2019; 37:3000.
  23. Dong XD, Tyler D, Johnson JL, et al. Analysis of prognosis and disease progression after local recurrence of melanoma. Cancer 2000; 88:1063.
  24. Rozeman EA, Menzies AM, van Akkooi ACJ, et al. Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial. Lancet Oncol 2019; 20:948.
  25. Menzies AM, Amaria RN, Rozeman EA, et al. Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC). Nat Med 2021; 27:301.
  26. Nan Tie E, Lai-Kwon J, Rtshiladze MA, et al. Efficacy of immune checkpoint inhibitors for in-transit melanoma. J Immunother Cancer 2020; 8.
  27. Vrouenraets BC, in't Veld GJ, Nieweg OE, et al. Long-term functional morbidity after mild hyperthermic isolated limb perfusion with melphalan. Eur J Surg Oncol 1999; 25:503.
  28. Calvo DB 3rd, Patt YZ, Wallace S, et al. Phase I-II trial of percutaneous intra-arterial cis-diamminedichloro platinum (II) for regionally confined malignancy. Cancer 1980; 45:1278.
  29. Calabro A, Singletary SE, Carrasco CH, Legha SS. Intraarterial infusion chemotherapy in regionally advanced malignant melanoma. J Surg Oncol 1990; 43:239.
  30. Eton O, East M, Legha SS, et al. Pilot study of intra-arterial cisplatin and intravenous vinblastine and dacarbazine in patients with melanoma in-transit metastases. Melanoma Res 1999; 9:483.
  31. Roberts MS, Wu ZY, Siebert GA, et al. Pharmacokinetics and pharmacodynamics of melphalan in isolated limb infusion for recurrent localized limb malignancy. Melanoma Res 2001; 11:423.
  32. Lindnér P, Thompson JF, De Wilt JH, et al. Double isolated limb infusion with cytotoxic agents for recurrent and metastatic limb melanoma. Eur J Surg Oncol 2004; 30:433.
  33. Minor DR, Allen RE, Alberts D, et al. A clinical and pharmacokinetic study of isolated limb perfusion with heat and melphalan for melanoma. Cancer 1985; 55:2638.
  34. Klaase JM, Kroon BB, van Geel BN, et al. Patient- and treatment-related factors associated with acute regional toxicity after isolated perfusion for melanoma of the extremities. Am J Surg 1994; 167:618.
  35. Cheng TY, Grubbs E, Abdul-Wahab O, et al. Marked variability of melphalan plasma drug levels during regional hyperthermic isolated limb perfusion. Am J Surg 2003; 186:460.
  36. Kroon HM, Moncrieff M, Kam PC, Thompson JF. Outcomes following isolated limb infusion for melanoma. A 14-year experience. Ann Surg Oncol 2008; 15:3003.
  37. Brady MS, Brown K, Patel A, et al. A phase II trial of isolated limb infusion with melphalan and dactinomycin for regional melanoma and soft tissue sarcoma of the extremity. Ann Surg Oncol 2006; 13:1123.
  38. 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; 15:2195.
  39. 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; 24:4196.
  40. Kroon HM, Coventry BJ, Giles MH, et al. Australian Multicenter Study of Isolated Limb Infusion for Melanoma. Ann Surg Oncol 2016; 23:1096.
  41. Beasley GM, Caudle A, Petersen RP, et al. A multi-institutional experience of isolated limb infusion: defining response and toxicity in the US. J Am Coll Surg 2009; 208:706.
  42. 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; 23:2330.
  43. Hafström 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; 9:2091.
  44. Andtbacka RH, Kaufman HL, Collichio F, et al. Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. J Clin Oncol 2015; 33:2780.
  45. Andtbacka RH, Ross M, Puzanov I, et al. Patterns of Clinical Response with Talimogene Laherparepvec (T-VEC) in Patients with Melanoma Treated in the OPTiM Phase III Clinical Trial. Ann Surg Oncol 2016; 23:4169.
  46. Andtbacka RHI, Collichio F, Harrington KJ, et al. Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III-IV melanoma. J Immunother Cancer 2019; 7:145.
  47. Weber J, Glutsch V, Geissinger E, et al. Neoadjuvant immunotherapy with combined ipilimumab and nivolumab in patients with melanoma with primary or in transit disease. Br J Dermatol 2020; 183:559.
Topic 7608 Version 40.0

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