Metastatic Melanoma

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Continuing Education Activity

Melanoma is the third most common cutaneous malignancy after basal cell carcinoma and squamous cell carcinoma. Melanoma is the fifth most common malignancy in males and the sixth most common malignancy in females. While most melanomas are detected at an early stage, a proportion of patients have metastatic disease at the time of diagnosis or develop metastasis at a later stage. The most common sites of metastasis are skin and subcutaneous tissue, followed by lungs, liver, bones, and brain. The treatment paradigm of metastatic melanoma has changed dramatically within the last few years with the advent of immune checkpoint inhibitors and targeted therapy. The treatment modalities currently used for metastatic melanoma include surgery, immunotherapy, targeted therapy, and chemotherapy. This activity explains when metastatic melanoma should be considered on a differential diagnosis, articulates how to properly evaluate this condition, and highlights the role of the interprofessional team in caring for patients with this condition.

Objectives:

  • Describe the evaluation of a patient with suspected metastatic melanoma.
  • Contrast the roles of the various treatment modalities for metastatic melanoma, such as surgery, radiation, and chemotherapy.
  • Explain the role of immune checkpoint inhibitors and BRAF targeted therapy for melanoma.
  • Outline how a well-coordinated, interprofessional team approach provides effective care to patients affected by metastatic melanoma.

Introduction

Incidence of primary cutaneous melanoma has increased steadily for several decades and remains the most lethal form of cutaneous neoplasm, but over the last three decades, the overall survival rates have remained relatively constant. From 2004 to 2009, the rates of stage IV metastatic cancer ranged from 26.4% to just 4.7%.[1][2] Mucosal and ocular melanoma typically have worse prognoses.[3] Melanoma was once considered among the most resistant cancers to traditional therapies such as chemotherapy, radiation, and even targeted therapies in their early stages. A dramatic improvement in quality of life and overall survival has resulted from new targeted immunotherapies for patients with metastatic melanoma. In this review, we discuss the current treatment landscape of metastatic melanoma. 

Melanoma is distinct from non-melanoma skin cancers in that it tends to spread locally, regionally, and distantly. An individual's risk of metastasis is directly related to the depth of invasion and ulceration of their primary lesion. The early stages of cancer metastasis involve invasion, angiogenesis, extravasation, dissemination, and colonization of the target organ. It is often believed that metastasis is a linear process from local disease to nodal metastasis to distant metastasis. Patients with node-negative disease and those who undergo sentinel lymph node basin can still present with distant metastatic disease, and complete lymph node dissection has not been proven to offer a survival benefit to patients with node-positive disease.[4]  

There are reports of the transfer of melanoma to the recipient from an organ transplant, even when the transplant was performed years after the donor was diagnosed with thin melanoma.[5] Such distant seeding suggests early metastatic melanoma may be common, and distant metastasis is likely controlled by a combination of microenvironment and immunity. A search for metastasis-specific genetic alterations in melanoma has not been particularly successful, although copy number alterations, MITF amplification, TERT promoter mutations, and CDKN2A loss occur at higher frequencies in metastatic melanomas than in primary melanomas.[6]  Melanoma has a propensity for spreading to the central nervous system (CNS)/brain, leading to high morbidity and resistance to therapy.[7][8]

Etiology

Certain types of melanoma are associated with cumulative solar damage (CSD). However, in some cases, the etiology is not always clear.[9] The 2018 WHO Classification of Melanoma categorizes melanomas into:

A. Melanomas Typically Associated with CSD

  • Pathway I. Superficial spreading melanoma/low-CSD melanoma
  • Pathway II. Lentigo maligna melanoma/high-CSD melanoma
  • Pathway III. Desmoplastic melanoma

B. Melanomas Not Consistently Associated with CSD Damage

  • Pathway IV. Spitz melanomas
  • Pathway V. Acral melanoma
  • Pathway VI. Mucosal melanomas
  • Pathway VII. Melanomas arising in congenital nevi
  • Pathway VIII. Melanomas arising in blue nevi
  • Pathway IX. Uveal melanoma

C. Nodular Melanoma (may occur in any or most of the pathways)

Four major variants of primary cutaneous melanoma are:

  • Superficial spreading melanoma
    • The most common type of melanoma 
    • Show hallmark melanoma features; asymmetry, irregular borders, color, ad increased diameter [10]
    • The prolonged radial growth phase, which is characterized by intraepidermal expansion 
    • No dermal invasion 
  • Nodular melanoma 
    • Located in chronically sun-exposed areas, head and neck. 
    • Histologically shows a vertical growth phase only, radial growth phase is absent 
    • Grow rapidly and usually present at an advanced Breslow depth 
    • It represents 15 to 20 % of primary melanomas but is responsible for 40 % of melanoma deaths. 
  • Lentigo maligna melanoma 
    • Elderly patients with chronically sun-damaged skin of the face 
    • Derived from ann in situ lentigo maligna precursor that presents as a slowly enlarging and changing brown to black macule with irregular borders 
  • Acral lentiginous melanoma 

Epidemiology

According to the SEER program, it is estimated that 100,350 new skin melanoma cases may be diagnosed in the United States in 2020. Every year in the United States, about 100,000 new cases of melanoma are diagnosed, and about 7000 patients die from metastases.[11] The incidence of melanoma has increased at a rapid pace compared to other cancers, especially in White race females.[12] 

Melanoma is caused by several factors, including environmental, genetic, and immunological ones.[13][14][15] In particular, research has focused on the activation of the immune system for the possibility of developing specific targeted therapies. Several genes are associated with melanoma predisposition: CDKN2A, CDK4, MC1R, and the genetic disorder xeroderma pigmentosum (XP), which results in the improper repair of UV-induced DNA damage and, therefore, a high mutation rate.[16][17][18][19]

Pathophysiology

Melanoma skin cancer has high metastatic spread risks as it originates from the melanocytes of the skin, which are neural crest-derived. Melanoma has a number of clinical attributes and risk factors that are well defined. Molecular genetics and next-generation sequencing have revealed that the BRAFV600E mutation plays a key role in oncogenic melanoma and that UV-induced DNA mutations result in melanoma formation. They have also uncovered many molecular events that occur throughout the development of melanoma. Immunotherapy and targeted therapies have significantly increased the cure rate for metastatic melanoma. Despite this, it remains a challenge to uncover the biology underlying therapeutic resistance and relapse. 

Melanocytes are neural crest-derived cells in the basal layer of the epidermis and located in skin, hair, uvea, mucosal epithelia, and meninges. The primary function of melanocytes is to synthesize melanin within melanosomes and transfer meaning via dendritic processes to neighboring keratinocytes. Melanocytes produce two forms of melanin pigment, eumelanin, and pheomelanin, which are both derived from precursor tyrosinase. [20]

Many factors can promote melanoma development, including exposure to ultraviolet (UV) rays.[21][22][23][24] People of the same ethnicity experience different rates of melanoma depending on their geographical location. Locations differ in terms of atmospheric absorption, latitude, altitude, cloud cover, and seasonality, thus impacting incident UV radiation.[25] 

Genetic factors may influence the pathogenesis of melanoma. The BRAF mutation has been detected in patients with melanoma without chronic sun damage in 2005 by Uhara et al.[26][27] Several studies have shown that nearly 40 to 50% of cutaneous melanomas have mutations in BRAF, a serine/threonine-protein kinase associated with RAS-RAF-MEK.[28] On activation of BRAF, extracellular signal-regulated kinase (ERK) is phosphorylated, one of the most common mutated isoforms of cancer.[28] The most common mutation is the V600E, although a different mutation called V600K has also been found in some cases.[28]  

History and Physical

The characteristic signs of early melanoma are recognized with the well-known ABCDE mnemonic as follows:[29]

  • “A” stands for Asymmetry
  • “B” stands for Border: irregular, ragged, notched, or blurred edges
  • “C” stands for Color: nonuniform
  • “D” stands for Diameter: larger than 6 millimeters
  • “E” stands for Evolving: changing in size, shape, or Color

Dermoscopy can also be an important tool in distinguishing benign or malignant lesions.[30][31] Once diagnosed, melanoma is staged using American Joint Committee on Cancer (AJCC) guidelines which guide treatment and prognosis.[32]

Evaluation

Metastatic melanoma can carry a poor prognosis. The 5- year survival rate is estimated to be 10 percent, and distant metastases have an even less favorable prognosis than local spread. Sites of metastases include skin, lungs, liver, and CNS. Prognosis can be affected by the site of clinical metastases. 

After a melanoma is diagnosed based on clinical findings and histopathologic confirmation, staging is performed based on guidelines established by AJCC. AJCC uses the TNM system to categorize melanoma from early stage to late stage.[32] Patients can be classified into five stages, 0, I, II, III, and IV; prognosis worsens with more severe staging. Stage zero is melanoma in situ, while stage IV is metastatic melanoma. Metastatic melanoma is the spread of primary melanoma cells to distant organs such as lymph nodes, lungs, liver, brain, and bones.[32][33] TNM system consists of the following components: Tumor thickness with or without ulceration, Nodal involvement, and metastasis.[32]

Screening for Metastases

Subcutaneous Tissue 

  • Subcutaneous nodules can be the first sign of hematogenous spread of melanoma.
  • CT of the subcutaneous tissue can reveal radiodense areas which are sharply contrasted against the radiolucent fat. 
  • The nodules enhance with contrast and may invade both surrounding muscle and soft tissue. 
  • A PET scan is superior to a CT scan for determining metastases to the subcutaneous tissue. 
  • Increased metabolism of melanoma metastases allows for its easy detection 

Lymph Nodes 

  • Regional lymph nodes are most commonly involved 
  • Incidence of lymphadenopathy consists of involvement of sentinel nodes correlates with Breslows thickness of the primary tumor.[34] 
    • <0.8 mm - the risk of nodal involvement is <1% 
    • 0.8-1.5 mm - the risk of nodal involvement is 8% 
    • 1.5-4.0 mm - the risk of nodal involvement is 23% 
    • >0.4 mm - the risk of nodal involvement is 36 % 
  • A PET scan is superior to a CT scan for identifying lymph node involvement

Pulmonary Involvement 

  • The most common cause of death in metastatic melanoma is pulmonary metastases causing respiratory failure.
  • Solitary metastases are resectable and considered potentially curable in up to 50 % of cases.
  • CT with contrast is used for screening pulmonary involvement. Metastatic nodules are distributed in the periphery, often well defined. Most are 1-2 cm in size. This can be followed by bronchoscopy followed by surgical resection.

CNS Involvement 

  • This is the second most common cause of metastatic melanoma-related deaths.
  • Hemorrhage is found in patients with brain metastases from melanoma.
  • MRI with contrast is more valuable than CT because of its remarkable ability to see acute, chronic, and subacute hemorrhages. In addition, Mri has higher sensitivity when imaging the brain stem, meninges, and spinal cord.

Liver 

  • The liver is the most common visceral organ affected by melanoma metastasis. Incidence correlates with Clark's level of the primary tumor. 
  • CT is considered the imaging of choice 
  • Metastases appearance on CT with contrast 

When suspicion is high for cutaneous melanoma, the best biopsy technique is an excisional biopsy, which allows a dermatopathologist to visualize the melanoma entirely and provide accurate staging, guiding treatment decisions and prognosis. The presence of multiple cutaneous melanomas should raise the possibility of metastatic disease. In extensive lesions that are difficult to completely excise, "scouting" biopsies within several areas of the lesion can be performed, although staging may depend on the excision specimen. 

Histopathology Findings

  • The asymmetric proliferation of atypical melanocytes with poorly circumscribed borders
  • Atypical melanocytes demonstrate pleomorphism, prominent nucleoli, and mitoses (dermal melanocytes in mitosis are an indication of a worse prognosis)
  • Ulceration, if present, is associated with a worse prognosis
  • Loss of melanocyte maturation (deeper cells are large and atypical as more superficial cells)
  • Pagetoid melanocytes
  • A lymphocytic response can be variable
  • Depth of invasion is the most important prognostic indicator. 
  • Breslow depth is measured from the top of the granular layer or ulcer base to the deepest melanoma cell measured in millimeters. 

Clark level- reported with staging but no longer used commonly. 

  • Level I: in situ (limited to within the epidermis)
  • Level II: invades the papillary dermis
  • Level III: fills the papillary dermis and reaches the reticular dermis.
  • Level IV: invades the reticular dermis
  • Level V: invades the subcutaneous fat

Features That Do Not Have a Role in the Current Staging

  • Regression (vascular fibrous tissue in the papillary dermis with or without melanophages)
  • Precursor nevus
  • Lymphatic or vascular invasion, usually in deeply invasive lesions
  • Melanoma subtypes are characterized by location, architecture, cell morphology, and associated background of solar damage 

American Joint Committee on Cancer (AJCC) Primary Tumor Staging (2018)Tumor

  • T1: ≤ 1 mm (a: < 0.8 mm without ulceration; b < 0.8 mm with ulceration, or 0.8 to 1 mm with or without ulceration)
  • T2: 1.1-2 mm (a: without ulceration; b: with ulceration)
  • T3: 2.1-4 mm (a: without ulceration; b: with ulceration)
  • T4: > 4 mm (a: without ulceration; b: with ulceration)[35]

Node

  • N0: 0 metastatic nodes
  • N1: 1 metastatic node or any number of in-transit, satellite, and/or microsatellite metastases
    • a: clinically occult, detected by sentinel lymph node [SLN] biopsy
    • b: clinically detected
    • c: no regional lymph node disease, but in-transit, satellite, and/or microsatellite metastases present
  • N2: 2-3 metastatic nodes or any number of in-transit, satellite, and/or microsatellite metastases with one tumor-involved node
    • a: clinically occult, detected by SLN biopsy
    • b: at least one node clinically detected
    • c: one clinically occult or clinically detected node and in-transit, satellite, and/or microsatellite metastases present
  • N3: 4+ metastatic nodes or any number of in-transit, satellite, and/or microsatellite metastases with two or more tumor-involved nodes, or any number of matted nodes without or with in-transit, satellite, and/or microsatellite metastases
    • a: clinically occult, detected by SLN biopsy
    • b: at least one node clinically detected or any number of matted nodes
    • c: 2 or more clinically occult or clinically detected nodes and/or presence of any number of matted nodes and in-transit, satellite, and/or microsatellite metastases present

Metastasis

  • M0: No distant metastasis
  • M1a: Distant skin, soft tissue including muscle, and/or nonregional nodal metastasis (0: normal lactate dehydrogenase [LDH]; 1: elevated LDH)
  • M1b: Lung metastasis (0: normal LDH; 1: elevated LDH)
  • M1c: Distant Metastasis to non-CNS visceral sites (0: normal LDH; 1: elevated LDH)
  • M1d: Distant Metastasis to CNS (0: normal LDH; 1: elevated LDH)

Sentinel lymph node (SLN) biopsy: Used only for staging and prognosis. National Comprehensive Cancer Network (NCCN) and the 2018 American Academy of Dermatology (AAD) guidelines recommend that, in general, SLN biopsy should be discussed and considered when the risk of metastasis is 5% or greater. Melanoma of T1b or higher grade, certain high-risk T1a melanomas (e.g., mitotic rate > two when associated with young age, lymphovascular invasion, or multiple adverse prognostic features), or when staging is uncertain (e.g., transected melanomas that may be T1b or higher). If the risk of metastasis is < 5%, NCCN guidelines do not recommend SLN biopsy. This procedure has not been shown to improve survival.

 Follow-up and surveillance: According to the 2018 AAD clinical practice guidelines, imaging and laboratory studies are not recommended for stage 0-II primary cutaneous melanomas. The use of lymph node (LN) ultrasound is appropriate when the SLN biopsy criteria are not met, when SLN biopsy cannot be performed or fails, when complete dissection of the LN is not performed with SLN biopsy results positive, or when an expert in the use of ultrasound for nodal surveillance is available.

Treatment / Management

Primary melanoma is treated with surgical removal of the tumor with wide excision or Mohs micrographic surgery, which provides a definitive cure. Late-stage melanoma leads to metastasis, can be difficult to treat, is refractile to therapies, and has high genomic variability.[36] By understanding how various genetic mutations contribute to the occurrence and progression of melanoma, new therapeutic approaches can be developed to target specific oncogenes. The treatment of metastatic melanoma has advanced significantly in the last decade. Vemurafenib/Zelboraf (PLX4720/PLX4032) is a highly selective small-molecule inhibitor of mutated BRAFV600E approved by the Food and Drug Administration for the treatment of advanced melanoma, but it was found that patients relapsed within 8 to 12 months.[37][38] 

Due to the reactivation of the MAPK pathway or other mutations, the treatment responses were short-lived.[39][40][41][42] When combined with other small molecule inhibitors of other MAPK components, such as MEK or ERK, BRAF inhibitors offer additional benefits over single-agent therapy and have increased toxicity. [42] To date, an inhibitor against RAS has not been developed. Christensen et al. reported tumor regression in KRAS-mutant tumor models using a KRASG12C inhibitor. In melanoma, KRAS mutations are rare. However, it is unclear if the recently developed KRASG12C inhibitor will be effective against KRAS-mutated melanomas. Furthermore, the mutated KRAS inhibitor was not tested for its efficacy against NRAS-mutated melanomas.[43][44] 

Surgical excision. Surgical excision margins depend on the tumor's depth of invasion. AAD clinical practice guidelines established in 2018 suggest:

  • In situ – margins 0.5 cm and up to 1 cm 
  • Less than 1 mm – margins 1 cm
  • 1-2 mm – margins 1 to 2 cm
  • 2-4 mm – margins 2 cm
  • Greater than 4 mm – margins 2 cm
  • For lentigo maligna melanoma on the face, ears, scalp, or other locations where a cosmetic outcome is important, Mohs micrographic surgery (MMS) or staged excisions have been used with low local recurrence rates. Although MMS is currently not the preferred approach to melanoma excision, it has certain advantages. On surgically constrained sites, margins less than 1 cm are not recommended for primary invasive melanoma. Permanent section analysis of the central MMS debulking specimen is recommended to identify and stage potential invasive melanoma.

Systemic Therapy

Due to melanoma's immunogenicity, it is a type of cancer amenable to immune checkpoint blockade (ICB) therapy.[45] It utilizes a patient's immune system to attack cancer cells, ensuring long-term immunity and durable survival. The idea of immunotherapy has been around a century with the first application of Coley's toxin, interferon (IFN), high dose interleukin-2 (IL-2), and the cancer vaccine, Bacillus-Calmette-Guerin (BCG) to treat melanoma. [46][47][48] Initially, these immunotherapies were non-specific. In recent years, monoclonal antibodies have increasingly been used to block immune checkpoints, such as CTLA-4, PD-1, and PD-L1, immune checkpoint molecules, and adoptive T-cell therapies.[46] Despite remarkable anti-tumor immune responses, these new immunotherapies only benefit a subset of patients.

Immune activity increases during infection to identify and eliminate the source of infection. The body controls the overactive immune response by activating immune checkpoints such as CTLA-4, PD-1, and PD-L1.[49][50][51][49] These immune checkpoints are utilized by cancer cells to suppress local and systemic immune responses. Cancer is a chronic disease, so T-cells within the lymph nodes continually encounter cancer antigens which result in the upregulation of CTLA-4 on their surface and the inhibition of proper T-cell activation, thereby disabling anti-tumor cytotoxic functions of T-cells.[52][53][54]

PD-1/PD-L1 functions within the tumor microenvironment, as the PD-1 receptor is expressed on the surface of T-cells, and the PD-L1 ligand is expressed on tumor cells.[47] PD-1/PD-L1 inhibits the cytotoxic effect of T cells against cancer cells.[47] It was shown that this axis contributes to T-cell anergy in lymph nodes draining tumors and that PD-1/PD-L1 interactions in these lymph nodes could serve as a prognostic factor for melanoma treatment outcomes.[55]

Monoclonal antibodies can block immuno-checkpoint interactions. Ipilimumab blocks CTLA-4, and Pembrolizumab/Nivolumab blocks PD-1. The FDA has approved these antibodies for patients with unresectable or metastatic melanoma. These agents have been shown to have positive and durable responses as well as improved survival in a subgroup of patients.[46][47][56][57][58] 

Stage III melanoma patients whose melanomas have been resected can undergo a variety of treatment regimens based on their BRAF genotype. A combination of BRAF and MEK inhibitors and anti-PD-1 is adjuvantly administered to patients with mutated BRAF, while patients with wild-type BRAF are treated with anti-PD-1 rather than anti-CTLA-4.[59] In combination with BRAF and MEK inhibitors, Vemurafenib and Cobimetinib, Atezolizumab has been approved for patients with unresectable or metastatic melanoma whose BRAF V600 mutation means they cannot be resected.[48] 

Immune Checkpoint Inhibitors

Immune checkpoint inhibitors are effective regardless of BRAF mutation status.[56][60][61][62] Options include nivolumab, pembrolizumab, or nivolumab/ipilimumab combination therapy. Nivolumab and pembrolizumab are the programmed cell death protein 1 (anti-PD-1) antibodies that interfere with ligand binding by the T-cell surface receptor PD-1, enhancing T-cell activation. Ipilimumab is a monoclonal antibody that binds and blocks the function of the immune checkpoint receptor CTLA-4.

BRAF/MEK Inhibitor Combination Therapy

BRAF-targeted therapy may be considered if the disease harbors a BRAF V600-activating mutation. Results from multiple randomized trials suggest that BRAF/MEK inhibitor combination therapy may enhance the duration of response compared with BRAF inhibitor monotherapy.[63][64][65][66][67][68][69][70] The combination therapy includes dabrafenib/trametinib, vemurafenib/cobimetinib, and encorafenib/binimetinib.

It is important to note that BRAF and MEK inhibitors may interact with radiation therapy and potentially increase toxicity.[71] Therefore, it is recommended to hold these medications for one or more days before and after stereotactic radiosurgery (SRS) and three or more days before and after fractionated stereotactic radiation therapy (SRT).

Local Therapy

Local therapy options for extracranial metastases include intralesional injection with talimogene laherparepvec (T-VEC), resection, or radiation.[72] Radiation therapy may be used for the palliative management of visceral, bone, and CNS metastases. SRS and/or whole-brain radiation therapy (WBRT) may be the primary modality or adjuvant following surgical resection for patients with brain metastases.

Follow-Up

Follow-up should be individualized.[72] Generally, chest x-ray, CT, brain MRI and/or PET/CT can be considered to screen for recurrent disease. More frequent surveillance with brain MRI is recommended for patients with prior brain metastases.

Supportive Care

Supportive care may be considered for those with poor performance status, disease progression despite proper treatment, or not fit for the preferred systemic treatment options.[72]

Differential Diagnosis

The differential diagnoses include:

  • Pigmented basal cell carcinoma
  • Seborrheic keratosis 
  • Squamous cell carcinoma (Bowen disease, pagetoid or pigmented)
  • Dermatofibroma
  • Other cutaneous metastases 
  • Paget disease 
  • recurrent melanocytic nevi

Staging

The American Joint Committee on Cancer (AJCC) TNM system is the staging system most often used for melanoma.[32] It is also known as the pathologic stage or the surgical stage and is based on the extent of the primary tumor (T), the spread to nearby lymph nodes (N), and then spread to distant sites (M). Patients may also be staged clinically as follows:

  • Stage 0: in-situ melanoma.
    • The cancer is confined to the epidermis (Tis).
    • It has not spread to local lymph nodes (N0) 
    • or distant parts of the body (M0) 
  • Stage I- Tumor is no more than 2 mm thick 
    • with or without ulceration (T1 or 
  • I: invasive melanoma and clinically negative nodes
  • III: palpable regional nodes, in-transit disease, or microsatellites
  • IV: distant metastases

Prognosis

In 2018, the 8th edition of the AJCC cancer staging system for cutaneous melanoma made several revisions to aid in clinical management and prognostic management. These changes have aided in treatment planning as metastatic involvement of viscera outside of the CNS.

Complications

Timely recognition and proper management of the potential treatment-related complications are crucial to alleviate patient morbidity and mortality.

Deterrence and Patient Education

Being diagnosed with metastatic melanoma and undergoing treatment can affect the emotional health of patients and their families, as their physical, spiritual, emotional, and interpersonal dimensions can be dramatically changed. Managing the psychological effects can be crucial to ensuring longer survivorship. Therefore, screening and assessment of the emotional and social concerns of patients and their families should be included in every follow-up visit.

Patients should be well-educated on the management plan, including the types of treatment, pros and cons of each treatment, side effects, and supportive measures. Counseling, referring the patients to the support groups, and collaborating with the mental health professionals can also be considered. Regular follow-up with oncologists and primary care physicians is also essential in monitoring treatment response and treatment-related toxicities.

Enhancing Healthcare Team Outcomes

Patient-centered interprofessional team-based care is vital in managing patients with metastatic melanoma. Well-implemented team-based care has the potential to improve the comprehensiveness, efficiency, effectiveness, coordination, and value of care in every step of management, from evaluation and diagnosis of the disease to management of complications related to disease or treatment, as well as regular follow-ups, and psychosocial support. This team will consist of clinicians (both physicians and mid-level practitioners), specialists (oncologists, system-specific specialists), oncology-specialized nursing staff, pharmacists (also preferable with oncology specialized training), and mental health professionals.

It is incumbent on all interprofessional team members treating patients with metastatic melanoma to contribute to the case from their specialized areas. Still, they must also work collaboratively as a team, using open information sharing and accurate record-keeping, and involving other team members as the patient's condition changes and in cases of therapeutic failure, medication adverse events, or any other concerns. In this way, all team members will have access to the same information regarding the patient's progress and can involve other team members as necessary to drive optimal patient outcomes and minimize the chances doe adverse events and treatment failure. [Level 5]

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Srinath Sundararajan

Author

Aye M. Thida

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Sujitha Yadlapati

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Supriya Koya

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