The incidence of melanoma has steadily risen in the United States since the 1970s, with an estimated 76,000 new cases in 2014 . Following surgical excision of the primary, recurrent disease can occur locally, regionally, or distantly. In-transit (IT) disease refers to metastases within the regional dermal and subdermal lymphatics near the primary melanoma but distal to the draining regional lymph node basin . Overall, approximately 4%–11% of melanoma recurrences present as IT metastases [3,4,5,6,7]. Several factors are associated with increased risk for IT metastases. These include patients with thicker primary melanomas (>1 mm), tumor ulceration, lymphovascular invasion (LVI), regional nodal involvement and location of the primary on a lower extremity [3,7,8,9]. The rates of IT disease vary substantially in the presence of these other factors, with higher incidences associated with more aggressive features.
Based on the 2010 7th edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, IT disease is categorized within the nodal staging of the TNM staging system . The presence of IT metastases correlates with clinical stage III melanoma, which is further divided within pathological staging into IIIB and IIIC, depending on primary tumor ulceration and whether lymph node metastases are concurrently involved (IIIB does not have lymph node metastases, whereas IIIC does). The prognosis of these stages varies but overall is quite poor, with reported five-year overall survival rates ranging from 20% to 60% [3,10,11,12,13]. IT disease itself is a risk factor for subsequent regional lymph node or metastatic disease, with up to 75% of patients with IT disease developing nodal or distant metastases [3,6]. Consequently, patients with IT disease should be carefully evaluated for additional sites of disease and undergo a detailed history and physical examination with scrutiny to the lymph node basins as well as staging imaging studies. The unfavorable outcomes and risk of advanced melanoma associated with IT disease reflect the relevance and need for effective therapies for these patients. In this review, the available treatments for IT melanoma of the extremity and their relative efficacy are discussed. With the emergence of improved systemic therapies, the role of regional therapies in comparison with newer, immunotherapeutic and targeted molecular agents are examined. Based upon the published data, treatment algorithms and justification for these treatment approaches are detailed.
2. Treatments for IT Melanoma
A wide range of options is available for IT melanoma. The most recent guidelines from the National Comprehensive Cancer Network (NCCN) outline these options (Table 1), which are similar for both IT disease that is synchronous with the primary tumor and recurrent IT disease . Options include surgical resection, intralesional and topical treatments, local radiation, regional therapies (comprised of isolated limb infusion (ILI) and isolated limb perfusion (ILP)), and systemic agents (including chemotherapies, interferon (IFN) and newer immunologic drugs, such as anti-CTLA4 and anti-PD-1 antibodies) [15,16,17]. Current clinical trials are also investigating multiple modality approaches, for example combining ILI with adjuvant ipilimumab (NCT01323517) or melanoma vaccines with ipilimumab (NCT00094653) [18,19]. As reflected by the NCCN guidelines, there is no consensus on the optimal approach . Treatment for a specific patient with IT melanoma may benefit from a multidisciplinary discussion to develop an individualized plan . When evaluating the options, a global understanding of the benefits and shortcomings of each approach should be considered (Table 2).
Table 1. Treatment Options for In-transit Melanoma.
|Local therapies||Surgical excision to clear margins|
|Intralesional injection (BCG, IFN, IL-2, oncolytic viruses)|
|Local ablation therapy|
|Regional therapies||Isolated limb perfusion with melphalan|
|Isolated limb infusion with melphalan|
|Small molecule inhibitors|
Table 2. In-transit Melanoma Treatment Variables.
|Local Therapies||Regional Therapies||Systemic Therapies|
Surgical resection to negative margins is considered the gold standard for IT melanoma. Unlike wide local excision (WLE) of the primary melanoma, 1–2 cm margins are not indicated as long as negative margins are obtained because IT disease already represents invasion into the subdermal lymphatics. This is a technically feasible option when the IT disease is limited to a single or few lesions, allowing for resection and subsequent closure of the wounds. However, in cases where there are multiple, widespread IT lesions along an extremity, surgical resection may not be appropriate as it may result in serious morbidity or significant deformity.
As noted earlier, IT disease is associated with an increased risk of nodal metastases. Some retrospective studies have reported an increased risk of IT disease following sentinel lymph node biopsy (SLNB) [21,22]. However, results from the prospective Multicenter Selective Lymphadenectomy Trial (MSLT-I) did not show a difference in the rate of either local recurrence or IT disease in patients with intermediate thickness melanoma who were randomly assigned to either observation or SLNB followed by completion lymphadenectomy in cases of a positive SLNB . Other studies support the findings of MSLT-I in that SLNB itself does not increase the risk of IT metastases [24,25]. When IT disease presents as a recurrence, SLNB may be considered. Repeat SLNB is technically feasible. Studies have shown that about one-third of patients with IT disease and no clinical nodal disease (or macrometastases) were found to have positive SLNB, even though the SLNB was negative when initially biopsied during excision of the primary lesion [26,27]. While SLNB in this setting has no definitive survival benefit, it does offer the potential for more complete staging and further treatment with completion lymph node dissection (CLND) of the draining nodal basin for local control. However, the benefits of SLNB and CLND in patients with IT disease may not be outweighed by the risks of surgery, namely post-operative lymphedema, particularly in the setting of nodal micrometastases. As an alternative to immediate CLND in the setting of known positive SLNB, the eagerly anticipated results of the Multicenter Selective Lymphadenectomy Trial II (MSLT-II) may support the close surveillance of the nodal basin with routine ultrasound (US) followed by delayed CLND if a recurrence is detected . Although patients with IT disease were excluded from MSLT-II, results of the trial may perhaps be extrapolated to this patient population since these patients already have stage N2c disease without macrometastases. Therefore, even in the presence of micrometastatic disease discovered from a SLNB, observation with close US may be a viable alternative to immediate CLND.
4. Lesional Therapies
Local lesional therapies include topical applications and intralesional injections [29,30]. Imiquimod is a Toll-like receptor agonist which generates antitumor activity through the induction of pro-inflammatory mediators . It is the typical topical drug used for melanoma, and it most often used for the lentigo maligna subtype [32,33]. In the setting of IT disease, imiquimod has shown beneficial effects alone and in combination with other intralesional therapies, although these studies are quite small [34,35]. In a small series of three patients, each with greater than 15 IT metastases, imiquimod resulted in >90% regression of IT lesions in two of the patients . Supplementation with intralesional interleukin-2 (IL-2) generated responses in the third patient. Another small series of nine patients with IT disease combined imiquimod with intralesional Bacille Calmette-Guerin (BCG) . Five patients had complete regression and one had a partial response. Patients were followed for median period of 35 months, at which point there were no recurrences. However, long-term data past years is lacking.
Intralesional injections are mainly comprised of BCG, interferon-alpha (IFN-α) and IL-2. BCG has been tested for recurrent disease. A meta-analysis of 15 studies with intralesional BCG in the adjuvant setting for patients with stage III melanoma showed complete response in 19%, partial responses in 26% and improved survival in 13% . Intralesional IFN-α has been tested in patients with advanced melanoma. While there are reported benefits in local responses, use of IFN-α has not been shown to be curative. In one of the largest studies of intralesional IFN-α, among 51 patients with metastatic melanoma who had a least one cutaneous metastasis, there were 24 (47.1%) complete or partial local responses . There are several studies that have investigated intralesional IL-2 for IT disease. In a retrospective analysis of 31 patients treated with IL-2, 10 patients (32.3%) developed a pathological complete response (pCR) and 17/31 (54.8%) had a partial response . Systematic reviews combining other small studies such as this one have shown good local control of IT disease, with up to 50% of treated patients achieving complete response [39,40].
A more contemporary, novel intralesional therapy is the small molecule PV-10, a drug containing 10% of the chemical rose bengal which is derived from a synthetic iodine dye . While it has a wide range of medical uses, this drug has been shown to have chemoablative properties in several cancer types [42,43]. Cell lysis in turn propagates exposure of tumor-associated antigen and leads to tumor-specific T cell-mediated responses, which is thought to mediate regression in uninjected cutaneous lesions through a bystander effect . Very small series have reported promising objective response rates in patients with metastatic melanoma [44,45]. A recent phase 2, multicenter, single arm trial of rose bengal in 80 patients with refractory stage III/IV melanoma showed an overall response rate of 51% and complete response rate of 26% . The durability of these responses was reported as a median of 4.0 months, with 8% of patients disease-free after 52 weeks.
In general, side effects of the different intralesional therapies are well tolerated . While this data appears impressive regarding the treated lesions, the ability of intralesional therapy to target microscopic IT lesions or deep deposits is limited. Therefore, the role of intralesional therapies often serves as an adjunct to more definitive treatments, and may function to palliate symptoms in patients who are too high risk to undergo more aggressive treatments.
5. Oncolytic Virus-Based Vaccines
Melanoma vaccines have long been sought as potential treatment options for systemic disease, although their use is currently limited to clinical trials and has not reached mainstream recommendations. Oncolytic viruses (OVs) have been developed to act through tumor tropic mechanisms resulting in direct oncolysis of tumor cells and subsequent antitumor events within the tumor microenvironment, potentiating systemic responses toward antitumor immunity . Animal melanoma models investigating recombinant adenoviruses or vaccinia pox viruses have shown promising antitumor responses [48,49,50]. Translation of these virus-based strategies to human trials has shown up-regulation of anti-tumor immunity in the setting of good patient tolerability with minimal side-effects, although these trials have been very small phase I/II studies [51,52,53]. Clinical trials are on-going to characterize and develop more fully the application of melanoma vaccines into standard therapy as single agents or in combination with existing treatments, which potentially may prove effective for patients with IT disease [19,54,55].
One new and very promising oncolytic viral construct is the herpes simplex virus type-1 based immunotherapy designated Talimogene laherparepvec (T-VEC). This virus selectively targets tumor cells and results not only in lytic destruction but also overcoming systemic anergy to tumor associated antigen through exposure of these antigens and production of GM-CSF to recruit macrophages to the tumor microenvironment . In the phase III OPTiM trial, T-VEC was compared to subcutaneous GM-CSF in patients with advanced melanoma where the primary endpoint was durable response rate (DRR) lasting at least six months. In the cohort, 30% had stage IIIB/C disease with the remainder having stage IV disease. DRR was reported in 16% of patients who received T-VEC compared to 2% of patients who received GM-CSF alone . The objective response rate (ORR) with T-VEC was 26% with and 11% CR versus a 6% ORR and 1% CR with GM-CSF alone . The therapy was well tolerated with the most common adverse events (AEs) being fatigue, chills and pyrexia occurring in 26% of the T-VEC group versus 13% in the GM-CSF alone group. Recent updates of this trial shows that OS has approached statistical significance with a median OS of 23.3 months with T-VEC versus 18.9 months with GM-CSF (HR = 0.787, 95% CI 0.62–1.00) . In addition, T-VEC has been shown to decrease the size of primary tumors facilitating resectability. A subset analysis of 37 patients treated with T-VEC at the primary who then underwent surgery showed that six patients converted from inoperable to operable, and 15/37 showed no evidence of disease . Further multimodal investigations with T-VEC are ongoing, including a phase Ib/II trial combining T-VEC with ipilimumab .
Radiation therapy (RT) is not typically indicated for IT disease. Conversely, it is more often utilized in patients with high-risk local-regional recurrence, including patients with desmoplastic melanoma or high nodal disease burden [60,61,62,63]. However, RT has a beneficial role in the palliation of local symptoms, such as bleeding, pain and fungating infections, which may result from extensive IT disease [64,65,66]. While not curative, high RT doses (>30 Gy) have been shown to obtain longer disease-free survival rates and overall survival compared to patients treated with lower RT doses (≤30 Gy) . RT is not without side-effects, which include short-term changes such as local edema, erythema, and desquamation as well as long-term risks such as fibrosis and later development of sarcoma [61,68]. Similar to lesional therapies, RT can be administered in an adjunctive or palliative role for patients with IT melanoma, although its use as a single modality treatment is minimally effective with the potential for significant toxicity.
7. Regional Therapy
Regional therapies for IT melanoma of the extremity include isolated limb perfusion (ILP) and isolated limb infusion (ILI). ILP has been used for extremity melanoma for over 50 years . It is typically performed in the operating room under general anesthesia. The technique includes vascular dissection of the inflow and outflow vessels to the targeted extremity (such as the iliac or femoral vessels in the lower limb or the axillary vessels in the upper limb), large bore cannulation of the vessels under direct vision, application of a proximal pneumatic tourniquet, external warming of the extremity using heating blankets and circulation of warmed chemotherapy. Temperatures during ILP typically reach 42 °C [70,71]. However, ILI typically cannot reach this degree of hyperthermia with temperatures closer to 40 °C [72,73
What is a Classification Essay?
In a classification essay, a writer organizes, or sorts, things into categories.
Three Steps to Effective Classification:
- Sort things into useful categories.
- Make sure all the categories follow a single organizing principle.
- Give examples that fit into each category.
This is a key step in writing a classification essay. To classify, or sort, things in a logical way, find the categories to put them into. For example, say you need to sort the stack of papers on your desk. Before you would put them in random piles, you would decide what useful categories might be: papers that can be thrown away; papers that need immediate action; papers to read; papers to pass on to other coworkers; or papers to file.
Thesis Statement of a Classification Essay
The thesis statement usually includes the topic and how it is classified. Sometimes the categories are named.
(topic)...(how classified)...(category) (category) (category)
Ex: Tourists in Hawaii can enjoy three water sports: snorkeling, surfing, and sailing.
How to Write an Effective Classification Essay
- Determine the categories. Be thorough; don't leave out a critical category. For example, if you say water sports of Hawaii include snorkeling and sailing, but leave out surfing, your essay would be incomplete because surfing is Hawaii's most famous water sport. On the other hand, don't include too many categories, which will blur your classification. For example, if your topic is sports shoes, and your organizing principle is activity, you wouldn't include high heels with running and bowling shoes.
- Classify by a single principle. Once you have categories, make sure that they fit into the same organizing principle. The organizing principle is how you sort the groups. Do not allow a different principle to pop up unexpectedly. For example, if your unifying principle is "tourist-oriented" water sports, don't use another unifying principle, such as "native water sports," which would have different categories: pearl diving, outrigger, or canoe racing.
- Support equally each category with examples. In general, you should write the same quantity, i.e., give the same number of examples, for each category. The most important category, usually reserved for last, might require more elaboration.
Common Classification Transitions
- The first kind, the second kind, the third kind
- The first type, the second type, the third type
- The first group, the second group, the third group
Remember: In a classification essay, the writer organizes, or sorts, things into categories. There are three steps to remember when writing an effective classification essay: organize things into useful categories, use a single organizing principle, and give examples of things that fit into each category.
Below are some sample classification essay topics:
- Classification of historical events in US
- Countries classification (territory, popularity, etc)
- Sport Cars Classification
- Most Popular TV Shows in America
- Classification of Physiological Diseases
You can choose essay topic for your classification essay you are familiar with.