The management of advanced-stage melanoma has changed dramatically with the introduction of systemic targeted therapy and immunotherapy. Patients with stage IV melanoma currently benefit from agents that are extremely effective, especially when compared with classic chemotherapeutic agents. The field is still evolving, and these newer agents are now used in patients with stage III disease, in the setting of adjuvant trials after resection of the disease bulk. Patients with bulky and numerous in-transit metastases form a very distinct subset of melanoma patients. The disease is classically staged as stage III, but because it is usually unresectable, a regional or systemic rather than a local approach is warranted. Isolated limb perfusion (ILP) is a regional technique that has been shown to provide high response rates and tumor control. The impressive results of ILP were obtained in the era of ineffective systemic agents. Now that this situation has profoundly changed, questions arise as to what the role of ILP is in the treatment of patients with melanoma in-transit metastases, which patients are ideal candidates for ILP, and whether ILP is here to stay—or will become obsolete in the near future.
During recent decades, the incidence of melanoma in the United States has increased to an estimated > 76,000 new cases in 2016. The vast majority (84%) of these patients present with disease confined to the local site. Surgery was, is, and will be the mainstay of treatment for these patients, resulting in excellent overall survival rates of > 90% (relative 5-year survival rate of 98.4%). Innovation in these patients with early-stage disease is not to be expected, nor is there a desperate need.
At the other end of the spectrum are the patients who present with metastatic disease. Patients with stage IV melanoma generally do not benefit from surgery; traditionally, systemic chemotherapy was offered, albeit with very limited success. This situation has changed fundamentally with the introduction of molecular targeted therapy and immune checkpoint inhibition. These therapies are currently recommended for first-line treatment of metastatic melanoma. Innovations over the past decade have been practice-changing for patients with stage IV disease.
About 9% of all patients with melanoma present with stage III disease. Patients in this category are the most challenging to treat. Regional metastases can present as satellite lesions close to the primary tumor location, as in-transit metastases between the site of the primary tumor and the draining lymph node basin, as micrometastases in the regional lymph nodes that can be detected only with a sentinel node biopsy, as clinically apparent lymph node metastases, or even as a combination of these features. This wide range of presentations corresponds with a wide range in expected 5- or 10-year survival. Patients with sentinel node micrometastases have 10-year life expectancies of about 70% (> 80% for patients with submicrometastases, according to the Rotterdam/Dewar criteria), whereas patients who present with clinically apparent nodes (eg, in the ilio-inguinal region) have overall survival rates of 10% to 20%. Consequently, the management of stage III melanoma should be tailored to the patient’s specific situation: a one-size-fits-all approach does not exist. It is for this patient subset that innovative approaches to treatment are most eagerly awaited.
In what can be called “early stage III” melanoma, life expectancy in the presence of satellite metastases or lymph node micrometastases is relatively high, and the goal of therapy can therefore be minimizing toxicity and morbidity while obtaining local control. This trend is apparent especially in the approach to the sentinel lymph node. Traditionally, patients with metastatic deposits in the sentinel node were offered completion lymph node dissection (CLND) to achieve maximal local control. It has become apparent that patients with micrometastases in their sentinel node may not benefit from further lymph node dissection and can thus be spared the additional morbidity. This concept is currently being prospectively evaluated in the European Organisation for Research and Treatment of Cancer (EORTC) 1208 (MiniTub) trial.
Furthermore, the results of a German prospective randomized trial of the value of CLND in patients with a positive sentinel lymph node biopsy strongly suggest that this procedure has no benefit, specifically for those patients with sentinel node metastases of < 1 mm. These results reinforce the matched cohort data from multiple centers that did not demonstrate a survival benefit for CLND after a positive sentinel node biopsy. The worldwide Multicenter Selective Lymphadenectomy Trial II (MSLT-II) will provide further insight into this intriguing question: given the morbidity of CLND, will less be more?
Patients with “advanced stage III” melanoma, such as those with multiple in-transit metastases or palpable nodes, require a different approach. Both in-transit metastases and multiple palpable nodes reflect extensive disease, and survival rates are correspondingly low. The prognosis of patients with > 4 palpable lymph nodes is no better than that of patients with stage IV disease. Recently, it has been suggested that more extensive surgery to the deep pelvic and obturator nodes does not improve outcomes for these patients.[8-10] In other words, the prognosis is dictated by the biology of the disease rather than by the extent of surgery.
The goal of therapy in these patients should therefore be to maximize overall survival and to achieve adequate local control. Local and systemic toxicity can be accepted but should obviously be minimized. In this patient category, the development of effective systemic chemotherapy may be resulting in serious paradigm shifts. A surgical approach is no longer the sole treatment option. Adjuvant immunotherapy (high-dose interferon alfa, pegylated interferon alfa-2b, and anti–cytotoxic T-lymphocyte–associated antigen 4 [anti–CTLA-4]) after CLND has been tested in phase III trials and has improved recurrence-free survival in the Eastern Cooperative Oncology Group (ECOG) 1684/Intergroup E1690,[11,12] EORTC 18991, and EORTC 18071 trials. Multiple trials are ongoing in this setting: eg, EORTC 1325/KEYNOTE 054 (anti–programmed death 1 [anti–PD-1]), Southwest Oncology Group (SWOG) S1404 (anti–PD-1 vs high-dose interferon alfa), ECOG 1609 (high-dose anti–CTLA-4 vs low-dose anti–CTLA-4 vs high-dose interferon alfa), BRIM8 (BRAF inhibitor), and COMBI-AD (BRAF inhibitor + MEK inhibitor). For patients with stage IIIC disease, systemic therapy is already registered as a potential first-line treatment, especially when the disease is deemed unresectable. Thus, effective systemic therapy for the treatment of stage III melanoma has emerged. Whether this influences treatment choice in stage III melanoma patients with in-transit metastases is the subject of this review.
In about 8% of melanoma patients with primary tumors of > 1 mm, in-transit metastases will develop during the course of the disease. These metastases result from tumor emboli trapped within the dermal and subdermal lymphatics and can occur anywhere between the site of the primary tumor and the draining regional lymph node basin. The median time between the diagnosis of the primary tumor and the development of in-transit metastases is about 15 months. The development of in-transit metastases is often a prelude to the appearance of systemic disease.
Various treatment options exist for melanoma in-transit metastases, as the presentation can range from a very few tiny lesions easily amenable to local excision, to > 100 extremely bulky lesions in previously extensively treated extremities. This wide range of clinical presentation requires a tailored approach for each patient. Whereas in some patients, resection of limited disease is part of a curative strategy, other patients may need treatment of in-transit metastases even in the presence of stage IV disease for purposes of palliation.
Finding the best treatment option for in-transit metastases can therefore be challenging. When the interval between the appearance of new lesions is short, when numerous and bulky metastases are present, or when multiple therapeutic modalities have failed, few options are available. The optimal treatment in these settings should be technically feasible, should have the potential for repetitive use if needed, and should limit both local and systemic toxicity.
Creech et al faced these challenges when they developed the concept of isolated limb perfusion (ILP) in 1958. At that time, melanoma was infamously refractory to any kind of systemic treatment. This led to the search for techniques that could deliver high concentrations of chemotherapy or other agents to the affected limb, without the risk of systemic toxicity. In this way, drug concentrations could potentially be made high enough to achieve an antitumor effect. As in-transit metastases of extremity melanomas are, by definition, confined to a limb, isolation of the affected limb from the systemic circulation would offer such an opportunity.
Isolation of the limb is achieved by surgical access to the artery and vein on the iliac, femoral, popliteal, axillary, or brachial level. The artery and vein are clamped and cannulated, after which the catheters can be connected to a heart-lung machine to get an oxygenated circuit. To further isolate the limb, a tourniquet is placed proximal to the site of the perfusion. The major concern with ILP is potential leakage of the effective agents into the systemic circulation. Therefore, leakage monitoring is mandatory, and a precordial scintillation probe is placed to detect any radioactively labeled albumin administered to the isolated circuit that has potentially leaked to the systemic circulation.
Once an isolated and leakage-free circuit is established, the perfusate is warmed in order to increase limb temperatures to between 38.5°C (101.3°F) and 39.5°C (103.1°F). This mild hyperthermia causes vasodilation in the dermal and subdermal tissue, which improves local drug delivery (twofold at 39.5°C [103.1°F] compared with 37.0°C [98.6°F]). A second effect is the idiosyncratic sensitivity of tumor cells to heat. Higher temperatures lead to increased drug uptake and cell death, but at the cost of severe local toxicity. True hyperthermia (> 40.0°C [104°F]) should therefore be avoided. When adequate tissue temperatures are reached, drugs can be added to the perfusate.
Melphalan (L-phenylalanine mustard) has been the standard drug for ILP because of its efficacy and toxicity profile. With the use of an isolated circuit, drug concentrations in the limb are 20 times higher than can be achieved systemically. Melphalan concentrations of 10 mg/L (leg) or 13 mg/L (arm) are considered standard doses. Melphalan-based ILP (M-ILP) was used for decades during the previous century, and complete response (CR) rates of 40% to 50% and overall response (OR) rates of 75% to 80% were achieved. These rates were unequaled by any other treatment modality.
Several attempts have been made to improve the response to ILP by using cytostatic drugs other than melphalan. Drugs commonly used in the treatment of systemically metastasized melanoma include dacarbazine and cisplatin, either alone or in a combination schedule. These drugs—among others—were tested in the ILP setting, but no drug or drug combination for patients with melanoma has achieved results superior to those of melphalan. Probably the only alternative schedule still in use is the combination of melphalan and actinomycin-D.
Probably the most influential adjustment of ILP was the introduction of tumor necrosis factor (TNF) by Lejeune and Liénard in 1988. TNF was isolated as an endogenous factor, especially active in inflammation, and with a necrotizing effect on tumor cells. TNF has a dual mechanism of action: the direct cytotoxic effect of high-dose TNF on tumor cells certainly plays a role in antitumor activity, but more importantly, the TNF effect on the so-called tumor-associated vasculature induces a rapid change in tumor morphology characterized by hemorrhagic necrosis. However, systemic use in patients with melanoma has been very disappointing. TNF turned out to be a potent mediator of septic shock; therefore, the systemic adverse effects (eg, fever, acute drop in vascular resistance leading to low blood pressure) are the major factors that obviate systemic application of this cytokine. Because the maximum tolerated dose of TNF in humans is 10 to 50 times lower than the dose required for antitumor effect, systemic as well as intralesional administration of TNF is not clinically feasible.
ILP combines the advantages of TNF antitumor activity with the avoidance of systemic effects. Moreover, the cytotoxic effects of TNF are enhanced in hyperthermic conditions and with the addition of alkylating chemotherapeutics, both of which are present during ILP.
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