Melanoma

Melanoma is a malignant tumor of melanocytes, which are the cells that make the pigment melanin and are derived from the neural crest. Although most melanomas arise in the skin, they may also arise from mucosal surfaces or at other sites to which neural crest cells migrate, including the uveal tract. Uveal melanomas differ significantly from cutaneous melanoma in incidence, prognostic factors, molecular characteristics, and treatment.

Cutaneous Melanoma   Staging   Treatment   Melanoma Drug Rx Summary   Uveal Melanoma  

Clinical Features

Melanoma occurs predominantly in adults, and more than 50% of the cases arise in apparently normal areas of the skin. Although melanoma can occur anywhere, including on mucosal surfaces and the uvea, melanoma in women occurs more commonly on the extremities, and in men it occurs most commonly on the trunk or head and neck.

Early signs in a nevus that would suggest a malignant change include the following:
•Darker or variable discoloration.
•Itching.
•An increase in size or the development of satellites.
•Ulceration or bleeding (later signs).

Diagnosis

A biopsy, preferably by local excision, should be performed for any suspicious lesions. Suspicious lesions should never be shaved off or cauterized. The specimens should be examined by an experienced pathologist to allow for microstaging.

Studies show that distinguishing between benign pigmented lesions and early melanomas can be difficult, and even experienced dermatopathologists can have differing opinions. To reduce the possibility of misdiagnosis for an individual patient, a second review by an independent qualified pathologist should be considered. Agreement between pathologists in the histologic diagnosis of melanomas and benign pigmented lesions has been studied and found to be considerably variable.

 

Prognostic Factors

Prognosis is affected by the characteristics of primary and metastatic tumors. The most important prognostic factors have been incorporated into the revised 2009 American Joint Committee on Cancer staging and include the following:

•Thickness and/or level of invasion of the melanoma.
•Mitotic index, defined as mitoses per millimeter.
•Ulceration or bleeding at the primary site.
•Number of regional lymph nodes involved, with distinction of macrometastasis and micrometastasis.
•Systemic metastasis.
•Site—nonvisceral versus lung versus all other visceral sites.
•Elevated serum lactate dehydrogenase level.

Patients who are younger, who are female, and who have melanomas on their extremities generally have better prognoses.
Microscopic satellites, recorded as present or absent, in stage I melanoma may be a poor prognostic histologic factor, but this is controversial. The presence of tumor infiltrating lymphocytes, which may be categorized as brisk, nonbrisk, or absent, is under study as a potential prognostic factor.
The risk of relapse decreases substantially over time, although late relapses are not uncommon.

 

Cellular and Molecular Classification of Melanoma

The descriptive terms for clinicopathologic cellular subtypes of malignant melanoma should be considered of historic interest only; they do not have independent prognostic or therapeutic significance. The cellular subtypes are the following:

•Superficial spreading.
•Nodular.
•Lentigo maligna.
•Acral lentiginous (palmar/plantar and subungual).
•Miscellaneous unusual types:
        •Mucosal lentiginous (oral and genital).
        •Desmoplastic
        •Verrucous.

Genomic Classification of Cutaneous melanoma

The Cancer Genome Atlas (TCGA) Network performed an integrative multiplatform characterization of 333 cutaneous melanomas from 331 patients. Using six types of molecular analysis at the DNA, RNA, and protein levels, the researchers identified four major genomic subtypes:

•BRAF mutant.
•RAS mutant.
•NF1 mutant.
•Triple wild-type (WT).

Genomic subtypes may suggest drug targets and clinical trial design, as well as guide clinical decision-making for targeted therapies. Refer to Table 1 for more information.

To date, targeted therapies have demonstrated efficacy and received the U.S. Food and Drug Administration (FDA) approval for the BRAF-mutant subtype of melanoma only.
Combination therapies with a BRAF plus a MEK inhibitor have shown improvement in outcomes over a single-agent inhibitor alone; yet, virtually all patients acquire resistance to therapy and relapse. (See the individual treatment sections).
Therefore, clinical trials remain an important option for patients with BRAF-mutant subtype, as well as other genomic subtypes of melanoma.

A variety of immunotherapies have been approved for the treatment of melanoma regardless of genetic subtype. (See the individual treatment sections.) The benefit of immunotherapy has not been associated with a specific mutation or molecular subtype. The TCGA analysis identified immune markers (in a subset within each molecular subtype) that were associated with improved survival and that may have implications for immunotherapy. Identification of predictive biomarkers remains an active area of research.

Melanoma Classification


Uveal melanoma

Uveal melanomas differ significantly from cutaneous melanomas. ln one series, 83% of 186 uveal melanomas were found to have a constitutively active somatic mutation in GNAQ or GNA11.
(See Uveal Melanoma -> Intraocular (Uveal) Melanoma Treatment)

 

 

Melanoma Staging

Stage Information for Melanoma
Clinical staging is based on whether the tumor has spread to regional lymph nodes or distant sites. For melanoma that is clinically confined to the primary site, the chance of lymph node or systemic metastases increases as the thickness and depth of local invasion increases, which worsens the prognosis. Melanoma can spread by local extension (through lymphatics) and/or by hematogenous routes to distant sites. Any organ may be involved by metastases, but lungs and liver are common sites.

The microstage of malignant melanoma is determined on histologic examination by the vertical thickness of the lesion in millimeters (Breslow classification) and/or the anatomic level of local invasion (Clark classification). The Breslow thickness is more reproducible and more accurately predicts subsequent behavior of malignant melanoma in lesions thicker than 1.5 mm and should always be reported.

Accurate microstaging of the primary tumor requires careful histologic evaluation of the entire specimen by an experienced pathologist.

Note: The American Joint Committee on Cancer (AJCC) has published the 8th edition of the AJCC Cancer Staging Manual, which includes revisions to the staging for this disease. Implementation of the 8th edition began in January 2018. The PDQ Adult Treatment Editorial Board, which maintains this summary, is reviewing the revised staging and will make appropriate changes as needed.

 

The American Joint Committee on Cancer (AJCC) staging system

The American Joint Committee on Cancer (AJCC) staging system is used to stage melanoma. The AJCC uses the TNM system to determine the melanoma stage. The overall stage is a combination of the T, N and M. This information should also be included on your pathology report.


T for primary tumor
The T category is based on primary tumor thickness.

•Tx: Tumor cannot be evaluated.
•T0: No evidence of cancer.

•Tis: Melanoma in situ describes a cancer that is confined to the outer layer of the skin.
•T1: Primary tumor depth is < 1.0mm
◦T1a: no ulceration and mitotic rate < 1/mm2
◦T1b: with ulceration or mitotic rate > 1/mm2

•T2: Primary tumor depth is between 1.01 and 2.0mm
◦T2a: no ulceration
◦T2b: with ulceration

•T3: Primary tumor depth is 2.01 to 4.0mm
◦T3a: no ulceration
◦T3b: with ulceration

•T4: Primary tumor depth is > 4.0mm
◦T4a: no ulceration
◦T4b: with ulceration


N for regional lymph nodes
The N category is based on lymph nodes containing or not containing cancer cells.

•Nx: Lymph nodes cannot be evaluated
•N0: No evidence of cancer in the lymph nodes

•N1: There are melanoma cells in 1 lymph node, further described by:
◦N1a: micrometastasis (can be seen by microscope, but not felt by physical exam)
◦N1b: macrometastases (can be felt by physical exam)

•N2: There are melanoma cells in 2 or 3 lymph nodes, further described by:
◦N2a: micrometastasis (can be seen by microscope, but not felt by physical exam)
◦N2b: macrometastases (can be felt by physical exam)
◦N2c: in transit or satellite lesions but NO positive lymph nodes

•N3: Any of the following:
◦> 4 lymph nodes with melanoma cells
◦2-3 positive lymph nodes that appear stuck together or "matted"
◦In transit or satellite lesions with any number of positive lymph nodes

M for distant metastasis
The M category is used to describe melanoma metastasis throughout the body.

•Mx: metastases cannot be evaluated
•M0: No evidence of metastases

•M1a: the melanoma has spread from the primary site to other areas of the skin or under the skin, or distant lymph nodes
•M1b: Melanoma has spread to the lungs
•M1c:
◦Melanoma has spread to any other organ with a normal LDH level (Lactate dehydrogenase)
◦Melanoma has spread to any site and LDH is elevated

Melanoma Stage description
0   The cancer is confined to the epidermis.
N0, M0   (This stage is also known as melanoma in situ.)
I   The cancer is no more than 2mm thick and might or might not be ulcerated.
N0, M0
  IA The tumor is less than 1 millimeter thick
  IB The tumor is either less than 1 millimeter thick and ulcerated, or
1–2 millimeters thick and not ulcerated.
II   The cancer is at least 1.01 mm and may be thicker than 4.0 mm. It might or might not be ulcerated.
N0, M0
  IIA The tumor is either 1–2 millimeters thick and ulcerated, or
2–4 millimeters thick and not ulcerated.
  IIB The tumor is either 2–4 millimeters thick and ulcerated, or
more than 4 millimeters thick and not ulcerated.
  IIC The tumor is more than 4 millimeters thick and is ulcerated.
These are aggressive tumors that are more likely to spread.
III  
  IIIA The cancer is no more than 2.0 mm thick. It might or might not be ulcerated.
It has spread to 3 or less lymph node(s), but it is so small that it is only seen under the microscope.
M0
  IIIB There is no sign of the primary cancer AND:
• Has spread to only one lymph node OR
• Has spread to very small areas of nearby skin (satellite tumors) or to skin lymphatic channels around the tumor (without reaching the lymph nodes).
M0
                OR
The cancer is no more than 4.0 mm thick. It might or might not be ulcerated AND:
• Has spread to only one lymph node OR
• Has spread to very small areas of nearby skin (satellite tumors) or to skin lymphatic channels around the tumor (without reaching the lymph nodes) OR
• Has spread to 2 or 3 lymph nodes.
M0
  IIIC There is no sign of the primary cancer AND:
• Has spread to one or more lymph nodes OR
• Has spread to very small areas of nearby skin (satellite tumors) or to skin lymphatic channels around the tumor (without reaching the lymph nodes) OR
• Has spread to any lymph nodes that are clumped together.
M0
                OR
The cancer is no more than 4.0 mm thick. It might or might not be ulcerated AND:
• Has spread to one or more lymph nodes OR
• Has spread to very small areas of nearby skin (satellite tumors) or to skin lymphatic channels around the tumor (without reaching the lymph nodes) OR
• Has spread to lymph nodes that are clumped together.
M0
                OR
The cancer is between 2.1 and 4.0mm OR thicker than 4.0 mm. It might or might not be ulcerated AND:
• Has spread to one or more lymph nodes OR
• Has spread to very small areas of nearby skin (satellite tumors) or to skin lymphatic channels around the tumor (without reaching the lymph nodes) OR
• Has spread to lymph nodes that are clumped together.
M0
                OR
The cancer is thicker than 4.0 mm and is ulcerated AND:
• Has spread to no more than 3 lymph nodes OR
• Has spread to very small areas of nearby skin (satellite tumors) or to skin lymphatic channels around the tumor (without reaching the lymph nodes).
M0
IIID The cancer is thicker than 4.0 mm and is ulcerated AND:
• Has spread to 4 or more lymph nodes OR
• Has spread to very small areas of nearby skin (satellite tumors) or to skin lymphatic channels around the tumor (without reaching the lymph nodes) OR
• Has spread to lymph nodes that are clumped together.
M0
IV   The cancer can be any thickness and might or might not be ulcerated. It might or might not have spread to nearby lymph nodes. It has spread to distant lymph nodes or organs such as the lungs, liver or brain.
M1

 

 

 

Melanoma Treatment Overview

Standard Treatment Options for Melanoma

Excision

Surgical excision remains the primary modality for treating melanoma. Cutaneous melanomas that have not spread beyond the site at which they developed are highly curable. The treatment for localized melanoma is surgical excision with margins proportional to the microstage of the primary lesion.

Lymph node management

Sentinel lymph node biopsy (SLNB)
Lymphatic mapping and SLNB can be considered to assess the presence of occult metastasis in the regional lymph nodes of patients with primary tumors larger than 1 to 4 mm, potentially identifying individuals who may be spared the morbidity of regional lymph node dissections and individuals who may benefit from adjuvant therapy.

To ensure accurate identification of the sentinel lymph node (SLN), lymphatic mapping and removal of the SLN should precede wide excision of the primary melanoma.

Multiple studies have demonstrated the diagnostic accuracy of SLNB, with false-negative rates of 0% to 2%. If metastatic melanoma is detected, a complete regional lymphadenectomy can be performed in a second procedure.

Complete lymph node dissection (CLND)
Patients can be considered for CLND if the sentinel node(s) is microscopically or macroscopically positive for regional control or considered for entry into the Multicenter Selective Lymphadenectomy Trial II (NCT00297895) to determine whether CLND affects survival. SLNB should be performed before wide excision of the primary melanoma to ensure accurate lymphatic mapping.

Adjuvant Therapy

High-dose interferon alpha-2b was approved by the U.S. Food and Drug Administration (FDA) in 1995 for the adjuvant treatment of patients with melanoma who have undergone a complete surgical resection but who are considered to be at a high risk of relapse (stages IIB, IIC, and III). However, prospective, randomized, multicenter treatment trials have demonstrated that high-dose interferon alpha-2b and pegylated interferon improve relapse-free survival but do not improve overall survival (OS).

Therapies that have improved OS in patients with recurrent or metastatic disease are now being tested as adjuvant therapy in clinical trials, including NCT01274338, NCT01667419, and NCT01682083.

Limb Perfusion

A completed, multicenter, phase III randomized trial (SWOG-8593) of patients with high-risk primary stage I limb melanoma did not show a disease-free survival or OS benefit from isolated limb perfusion with melphalan, when compared with surgery alone.

Systematic Treatment for Unresectable Stage III, Stage IV, and Recurrent Disease

Although melanoma that has spread to distant sites is rarely curable, treatment options are rapidly expanding. Two approaches—checkpoint inhibition and targeting the mitogen-activated protein kinase pathway—have demonstrated improvement in OS in randomized trials in comparison to dacarbazine (DTIC). Although none appear to be curative when used as single agents, early data of combinations are promising. Given the rapid development of new agents and combinations, patients and their physicians are encouraged to consider treatment in a clinical trial for initial treatment and at the time of progression.


Chemotherapy

DTIC
DTIC was approved in 1970 on the basis of overall response rates. Phase III trials indicate an overall response rate of 10% to 20%, with rare complete responses observed. An impact on OS has not been demonstrated in randomized trials.[15-18] When used as a control arm for recent registration trials of ipilimumab and vemurafenib in previously untreated patients with metastatic melanoma, DTIC was shown to be inferior for OS.

Temozolomide
Temozolomide, an oral alkylating agent, appeared to be similar to intravenous DTIC in a randomized phase III trial with a primary endpoint of OS; however, because the trial was designed to demonstrate the superiority of temozolomide, which was not achieved, the trial was left with a sample size that was inadequate to provide statistical proof of noninferiority.

Immunotherapy

Checkpoint inhibitors

Three checkpoint inhibitors—pembrolizumab, nivolumab, and ipilimumab—are now approved by the FDA. Each has demonstrated the ability to impact OS against different comparators in unresectable or advanced disease. (Refer to the Pembrolizumab, the Nivolumab, and the Ipilimumab sections in the Unresectable Stage III, Stage IV, and Recurrent Melanoma Treatment section of this summary for more information.) Multiple phase III trials are in progress to determine optimal sequencing of immunotherapies, immunotherapy with targeted therapy, and whether combinations of immunotherapies or immunotherapy plus targeted therapy are superior for increasing OS.

Interleukin-2 (IL-2)

IL-2 was approved by the FDA in 1998 on the basis of durable complete response (CR) rates in a minority of patients (6%–7%) with previously treated metastatic melanoma in eight phase I and II studies. Phase III trials comparing high-dose IL-2 with other treatments and providing an assessment of relative impact on OS have not been conducted.

Signal-transduction inhibitors

Studies to date indicate that both BRAF and MEK inhibitors can significantly impact the natural history of melanoma, although they do not appear to be curative as single agents.

BRAF inhibitors
Vemurafenib
Vemurafenib, approved by the FDA in 2011, has demonstrated an improvement in progression-free survival (PFS) and OS in patients with unresectable or advanced disease. Vemurafenib is an orally available, small-molecule, selective BRAF V600E kinase inhibitor, and its indication is limited to patients with a demonstrated BRAF V600E mutation by an FDA-approved test.

Dabrafenib
Dabrafenib, an orally available, small-molecule, selective BRAF inhibitor that was approved by the FDA in 2013, showed improvement in PFS when compared with DTIC in an international, multicenter trial (BREAK-3 [NCT01227889]).

MEK inhibitors
Trametinib
Trametinib is an orally available, small-molecule, selective inhibitor of MEK1 and MEK2 that was approved by the FDA in 2013 for patients with unresectable or metastatic melanoma with BRAF V600E or K mutations. Trametinib demonstrated improved PFS over DTIC.

Cobimetinib
Cobimetinib is an orally available, small-molecule, selective MEK inhibitor that was approved by the FDA in 2015 for use in combination with the BRAF inhibitor vemurafenib. (Refer to the Combination signal-transduction inhibitor therapy section of this summary for more information.)

c-KIT inhibitors
Early data suggest that mucosal or acral melanomas with activating mutations or amplifications in c-KIT may be sensitive to a variety of c-KIT inhibitors. Phase II and phase III trials are available for patients with unresectable stage III or stage IV melanoma harboring the c-KIT mutation.

Combination signal-transduction inhibitor therapy
In 2014, the combination of dabrafenib and trametinib received accelerated approval from the FDA for patients with unresectable or metastatic melanomas that carry the BRAF V600E or V600K mutation. The combination demonstrated improved durable response rates over single-agent dabrafenib. Full approval is pending completion of ongoing clinical trials and demonstration of clinical benefit on OS.

In 2015, the combination of vemurafenib and cobimetinib was also approved by the FDA for patients with unresectable or metastatic melanomas that carry the BRAF V600E or V600 K mutation. Published phase III data support improved PFS of another combination of BRAF and MEK inhibitors versus BRAF inhibitor plus placebo; dabrafenib plus trametinib compared with dabrafenib plus placebo. OS data are immature.

Palliative local therapy

Melanoma metastatic to distant, lymph node–bearing areas may be palliated by regional lymphadenectomy. Isolated metastases to the lung, gastrointestinal tract, bone, or sometimes the brain may be palliated by resection, with occasional long-term survival.

 

Treatment Options for Melanoma

Stage 0 Melanoma Treatment

Standard Treatment Options for Stage 0 Melanoma
Excision: Patients with stage 0 disease may be treated by excision with minimal, but microscopically free, margins.

Stage 1 Melanoma Treatment

Standard Treatment Options for Stage 1 Melanoma
Excision: Evidence suggests that lesions no thicker than 2 mm may be treated conservatively with radial excision margins of 1 cm.
Depending on the location of the melanoma, most patients can now have the excision performed on an outpatient basis.
Evidence: See PDQ (4 randomized trials)
Lymph node management: Elective regional lymph node dissection is of no proven benefit for patients with stage I melanoma.
Lymphatic mapping and sentinel lymph node biopsy (SLNB) for patients who have tumors of intermediate thickness and/or ulcerated tumors may identify individuals with occult nodal disease. These patients may benefit from regional lymphadenectomy and adjuvant therapy.
Evidence (immediate lymphadenectomy vs. observation with delayed lymphadenectomy): See PDQ (2 randomized trials)

Treatment options under clinical evaluation for patients with stage I melanoma:
Clinical trials evaluating new techniques to detect submicroscopic SLN metastasis. Because of the higher rate of treatment failure in the subset of clinical stage I patients with occult nodal disease, clinical trials have evaluated new techniques to detect submicroscopic SLN metastasis to identify patients who may benefit from regional lymphadenectomy with or without adjuvant therapy.

Stage 2 Melanoma Treatment

Standard Treatment Options for Stage 2 Melanoma: Excision with or without lymph node management
Excision:
For melanomas with a thickness between 2 mm and 4 mm, surgical margins need to be 2 cm to 3 cm or smaller.
Few data are available to guide treatment in patients with melanomas thicker than 4 mm; however, most guidelines recommend margins of 3 cm whenever anatomically possible.
Depending on the location of the melanoma, most patients can have the excision performed on an outpatient basis.
Evidence: See PDQ (2 randomized trials)
Lymph node management: (See PDQ)
    Lymphatic mapping and sentinel lymph node biopsy (SLNB)
    Regional lymphadenectomy

Adjuvant therapy: (See PDQ)
    High-dose interferon

Treatment options under clinical evaluation for patients with stage II melanoma:
Postsurgical adjuvant treatment (e.g., with interferons) has not been shown to affect survival.
Clinical trials are testing therapies of postsurgical adjuvant treatment that have improved OS in patients with stage IV disease, including NCT01274338, NCT01667419, and NCT01682083.

Resectable Stage III Melanoma Treatment

Standard Treatment Options for Resectable Stage III Melanoma
1. Excision with or without lymph node management.
2. Adjuvant therapy.
    a. Immunotherapy. (■ Checkpoint inhibitors. ■ Interferon alpha-2b.)
    b. Combination signal transduction inhibitors. (■ Dabrafenib plus trametinib.)

1. Excision with or without lymph node management.
Excision The primary tumor may be treated with wide local excision with 1-cm to 3-cm margins, depending on tumor thickness and location. Skin grafting may be necessary to close the resulting defect.
Lymph node management
    Sentinel lymph node biopsy (SLNB) Lymphatic mapping and SLNB can be considered to assess the presence of occult metastases in the regional lymph nodes of patients with primary tumors larger than 1 mm to 4 mm, potentially identifying individuals who may be spared the morbidity of regional lymph node dissections and individuals who may benefit from adjuvant therapy.
To ensure accurate identification of the SNL, lymphatic mapping and removal of the SLN should precede wide excision of the primary melanoma.
Multiple studies have demonstrated the diagnostic accuracy of SLNB, with false-negative rates of 0% to 2%. If metastatic melanoma is detected, a complete regional lymphadenectomy can be performed in a second procedure.
    Complete lymph node dissection (CLND) Patients can be considered for CLND if the sentinel node(s) is microscopically or macroscopically positive for regional control or considered for entry into the Multicenter Selective Lymphadenectomy Trial II to determine whether CLND affects survival. SLNB should be performed prior to wide excision of the primary melanoma to ensure accurate lymphatic mapping.

2. Adjuvant therapy
Adjuvant therapeutic options for patients at high risk are expanding and building on advances seen in the metastatic setting. Prospective, randomized, multicenter treatment trials have demonstrated a clinically significant impact on relapse-free survival (RFS) with checkpoint inhibitors and combination signal transduction inhibitor therapy. Data to date support an impact on overall survival (OS) for ipilimumab versus placebo; however, data for OS are still maturing for nivolumab versus active control (ipilimumab) and dabrafenib plus trametinib. As in the metastatic setting, adjuvant immunotherapy has shown an impact on clinically relevant endpoints in patients with and without BRAF mutations.
Clinical trials of immunotherapy as a single agent or in combination with vaccines, therapies targeting specific mutations, and others remain important options for patients.
Immunotherapy (See PDQ for evidence)
Checkpoint Inhibitors: Nivolumab, Ipilimumab, Interferon alpha-2b
Combination signal transduction inhibitors (See PDQ for evidence)
Dabrafenib plus trametinib

Treatment Options Under Clinical Evaluation for Resectable Stage III Melanoma
1. Trials of combination immunotherapies, including vaccines.
2. Trials of adjuvant therapies that target a known mutation, e.g., c-KIT.
3. Intralesional therapies.

 

Unresectable Stage III, Stage IV, and Recurrent Melanoma Treatment


Treatment Options for Unresectable Stage III, Stage IV, and Recurrent Melanoma
1. Intralesional therapy.

2. Immunotherapy.
a. Checkpoint inhibitors.
    ■ Anti–PD-1 (programmed cell death-1) and PD-L1 (programmed death-ligand 1).
    ■ Anti–CTLA-4 (ipilimumab).
b. High-dose interleukin-2 (IL-2).
c. Dual immunomodulation.
d. Dual checkpoint inhibition.

3. Signal-transduction inhibitors.
a. BRAF (V-raf murine sarcoma viral oncogene homolog B1) inhibitors (for patients who test positive for the BRAF V600 mutation). ■ Vemurafenib. ■ Dabrafenib.
b. MEK inhibitors. ■ Trametinib. ■ Cobimetinib.
c. KIT inhibitors.
d. ■ Multikinase inhibitors.
    Combination therapy with signal-transduction inhibitors. ■ BRAF plus MEK inhibitors. - Dabrafenib plus trametinib. - Vemurafenib plus cobimetinib.

4. Chemotherapy.

5. Palliative local therapy.

Two approaches—checkpoint inhibition and targeting the mitogen-activated protein kinase (MAPK) pathway—have demonstrated improvement in overall survival (OS) in randomized trials versus the use of dacarbazine (DTIC) or in comparison to DTIC. Given the rapid development of new agents and combinations, patients and their physicians are encouraged to consider treatment in a clinical trial for initial treatment and at the time of progression.


1. Intralesional therapy
Talimogene laherparepvec (T-VEC) (See PDQ for evidence)
T-VEC is a genetically modified, herpes simplex virus type 1 (HSV1) oncolytic therapy approved for local intralesional injection into unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma that recurs after initial surgery. T-VEC is designed to replicate within tumors, causing lysis, and to produce granulocyte-macrophage colony-stimulating factor (GM-CSF). Release of antigens together with virally derived GM-CSF may promote an antitumor immune response; however, the exact mechanism of action is unknown.

The approval of T-VEC by the U.S. Food and Drug Administration (FDA) is based on data that demonstrated shrinkage of lesions; however, improvement of OS or an effect on visceral metastases or improvement in quality of life has not been shown.

Precautions: T-VEC is a live, attenuated herpes simplex virus and may cause life-threatening, disseminated herpetic infection. It is contraindicated in immunocompromised or pregnant patients. Healthcare providers and close contacts should avoid direct contact with injected lesions. Biohazard precautions for preparation, administration, and handling are provided in the label.

2. Immunotherapy
a) Checkpoint inhibitors: (See PDQ for evidence)
■ Anti–PD-1 and PD-L1
The programmed-death 1 (PD-1) pathway is a key immunoinhibitory mediator of T-cell exhaustion. Blockade of this pathway can lead to T-cell activation, expansion, and enhanced effector functions.
PD-1 has two ligands, PD-L1 and PD-L2.
Two anti–PD-1 antibodies, pembrolizumab and nivolumab, have gained accelerated approval from the FDA in 2014, based on DRRs in previously treated patients. Full approval will depend on a demonstration of improvement in progression-free survival (PFS), OS, or improved quality of life in randomized trials.

■ Anti–CTLA-4
Ipilimumab
Ipilimumab is a human monoclonal antibody that binds to CTLA-4, thereby blocking its ability to down-regulate T-cell activation, proliferation, and effector function.

Ipilimumab has demonstrated clinical benefit by prolonging OS in randomized trials, and was approved by the FDA in 2011. Two prospective, randomized, international trials, one each in previously untreated and treated patients, supported the use of ipilimumab.

b) High-dose IL-2 (See PDQ for evidence)
IL-2 was approved by the FDA in 1998 on the basis of durable CRs in eight phase I and II studies. Phase III trials comparing high-dose IL-2 to other retreatments, providing an assessment of relative impact on OS, have not been conducted.

c) Dual immunomodulation (See PDQ for evidence)
T-cells coexpress several receptors that inhibit T-cell function. Preclinical data and early clinical data suggest that coblockade of the two inhibitory receptors, cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed death-1 (PD-1), may be more effective than blockade of either alone. This has led to a phase III trial (NCT01844505) comparing each single agent with the combination.

d) Dual checkpoint inhibition (See PDQ for evidence)
CTLA-4 inhibitor plus PD-1 inhibitor

3. Signal-transduction inhibitors
Studies to date indicate that both BRAF and MEK (mitogen-activated ERK-[extracellular signal-regulated kinase] activating kinase) inhibitors, as single agents and in combination, can significantly impact the natural history of melanoma, although they do not appear to provide a cure.

a) BRAF inhibitors (See PDQ for evidence)
■ Vemurafenib
(Name: V600E mutated BRAF Inhibition)
Vemurafenib is an orally available, small molecule, selective BRAF kinase inhibitor that was approved by the FDA in 2011 for patients with unresectable or metastatic melanoma who test positive for the BRAF V600E mutation.

Treatment with vemurafenib is discouraged in wild-type BRAF melanoma because data from preclinical models have demonstrated that BRAF inhibitors can enhance rather than down-regulate the MAPK pathway in tumor cells with wild-type BRAF and upstream RAS mutations.
■ Dabrafenib
Dabrafenib is an orally available, small molecule, selective BRAF inhibitor that was approved by the FDA in 2013 for patients with unresectable or metastatic melanoma who test positive for the BRAF V600E mutation as detected by an FDA-approved test. Dabrafenib and other BRAF inhibitors are not recommended for treatment of BRAF wild-type melanomas, as in vitro experiments suggest there may be a paradoxical stimulation of MAPK signaling resulting in tumor promotion.

b) MEK inhibitors (See PDQ for evidence)
■ Trametinib.
Trametinib is an orally available, small-molecule, selective inhibitor of MEK1 and MEK2. BRAF activates MEK1 and MEK2 proteins, which in turn, activate MAPK. Preclinical data suggest that MEK inhibitors can restrain growth and induce cell death of some BRAF-mutated human melanoma tumors. BRAF activates MEK1 and MEK2 proteins, which, in turn, activate MAPK.

In 2013, trametinib was approved by the FDA for patients with unresectable or metastatic melanoma with BRAF V600E or K mutations, as determined by an FDA-approved test.

■ Cobimetinib
Cobimetinib is a small-molecule, selective MEK inhibitor that was approved by the FDA in 2015 for use in combination with the BRAF inhibitor vemurafenib. (See the Combination therapy with signal-transduction inhibitors section.)

c) KIT inhibitors (See PDQ for evidence)
Early data suggest that mucosal or acral melanomas with activating mutations or amplifications in c-KIT may be sensitive to a variety of c-KIT inhibitors. Phase II and phase III trials are available for patients with unresectable stage III or stage IV melanoma harboring the c-KIT mutation.

d) ■Sorafenib
The multikinase inhibitor sorafenib has activity against both the vascular endothelial growth-factor signaling and the Raf/MEK/ERK pathway.
This agent had minimal activity as a single agent in melanoma treatment. Two large, multicenter, placebo-controlled, randomized trials of carboplatin and paclitaxel plus or minus sorafenib showed no improvement over chemotherapy alone as either first-line treatment or second-line treatment.

d) Combination therapy with signal-transduction inhibitors
Resistance to BRAF inhibitors, in patients with BRAF V600 mutations, may be associated with reactivation of the MAPK pathway. Combinations of signal-transduction inhibitors that block different sites in the same pathway or sites in multiple pathways are an active area of research.

BRAF inhibitor plus MEK inhibitor
dabrafenib plus trametinib (See PDQ for evidence)
vemurafenib plus cobimetinib (See PDQ for evidence)


4. Chemotherapy
DTIC was approved in 1970 on the basis of ORRs. Phase III trials indicate an ORR of 10% to 20%, with rare CRs observed. An impact on OS has not been demonstrated in randomized trials. When used as a control arm for recent registration trials of ipilimumab and vemurafenib in previously untreated patients with metastatic melanoma, DTIC was shown to be inferior for OS.

Temozolomide, an oral alkylating agent that hydrolyzes to the same active moiety as DTIC, appeared to be similar to DTIC (IV administration) in a randomized, phase III trial with a primary endpoint of OS; however, the trial was designed for superiority, and the sample size was inadequate to prove equivalency.

The objective response rate to DTIC and the nitrosoureas, carmustine and lomustine, is approximately 10% to 20%. Responses are usually short-lived, ranging from 3 to 6 months, although long-term remissions can occur in a limited number of patients who attain a CR.

A randomized trial compared IV DTIC with temozolomide, an oral agent; OS was 6.4 months for DTIC versus 7.7 months for temozolomide (HR, 1.18; 95% CI, 0.92–1.52). While these data suggested similarity between DTIC and temozolomide, no benefit in survival has been demonstrated for either DTIC or temozolomide; therefore, demonstration of similarity did not result in approval of temozolomide by the FDA.[Level of evidence: 1iiA]

An extended schedule and escalated dose of temozolomide was compared with DTIC in a multicenter trial by the European Organisation for Research and Treatment of Cancer (EORTC) (EORTC-18032 [NCT00101218]) randomly assigning 859 patients. No improvement was seen in OS or PFS for the temozolomide group, and this dose and schedule resulted in more toxicity than standard-dose, single-agent DTIC.[Level of evidence: 1iiA]

Two randomized, phase III trials in previously untreated patients with metastatic melanoma (resulting in FDA approval for vemurafenib and ipilimumab) included DTIC as the standard therapy arm. Both vemurafenib (in BRAF V600 mutant melanoma) and ipilimumab showed superior OS compared with DTIC in the two separate trials.

Other agents with modest, single-agent activity include vinca alkaloids, platinum compounds, and taxanes.

Attempts to develop combination regimens that incorporate chemotherapy (e.g., multiagent chemotherapy, combinations of chemotherapy and tamoxifen, and combinations of chemotherapy and immunotherapy) have not demonstrated an improvement in OS.

A published data meta-analysis of 18 randomized trials (15 of which had survival information) that compared chemotherapy with biochemotherapy (i.e., the same chemotherapy plus interferon alone or with IL-2) reported no impact on OS.[Level of evidence:1iiA]

5. Palliative local therapy
Melanoma metastatic to distant, lymph node–bearing areas may be palliated by regional lymphadenectomy. Isolated metastases to the lung, gastrointestinal tract, bone, or sometimes the brain may be palliated by resection, with occasional long-term survival.

Although melanoma is a relatively radiation-resistant tumor, palliative radiation therapy may alleviate symptoms. Retrospective studies have shown that symptom relief and some shrinkage of the tumor with radiation therapy may occur in patients with the following:
• Multiple brain metastases.
• Bone metastases.
• Spinal cord compression.
The most effective dose-fractionation schedule for palliation of melanoma metastatic to the bone or spinal cord is unclear, but high-dose-per-fraction schedules are sometimes used to overcome tumor resistance. (See the PDQ summary on Cancer Pain.)

Treatment Options Under Clinical Evaluation for Unresectable Stage III, Stage IV, and Recurrent Melanoma

1.Immunotherapy—single agent, and combination immunomodulation.

2.Targeted therapy—single-agent and combination therapy.
a.Signal-transduction inhibitors, including P13K (phosphoinositide-3 kinase) and Akt (protein kinase B) inhibitors, CDK (cyclin-dependent kinase) in addition to BRAF and MEK.
b.Antiangiogenesis agents. Preclinical data suggest that increased vascular endothelial growth factor production may be implicated in resistance to BRAF inhibitors.
c.Targeted therapy for specific melanoma populations.
    • In smaller subsets of melanoma, activating mutations may occur in NRAS (neuroblastoma RAS viral [v-ras] oncogene homolog) (15%–20%), c-KIT (28%–39% of melanomas arising in chronically sun-damaged skin, or acral and mucosal melanomas), and CDK4 (cyclin-dependent kinase 4) (<5%), whereas GNAQ is frequently mutated in uveal melanomas. Drugs developed to target the pathways activated by these mutations are currently in clinical trials.

3.Combinations of immunotherapy and targeted therapy.
4. Intralesional injections (for example, oncologic viruses).
5.Complete surgical resection of all known disease versus best medical therapy.
6.Isolated limb perfusion for unresectable extremity melanoma.
7.Systemic therapy for unresectable disease.

 

 

Current Clinical Trials

1. NCI advanced clinical trial search. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria.
2. General information about clinical trials.

 

 

Melanoma Drug Treatment Summary

Adjuvant therapy for stage II and stage III melanoma

NCCN recommendations for adjuvant therapy:
• Observation OR
• Nivolumab for resected stage IIIB/IIIC (Category 1) - Preferred regimen; OR
• dabrafenib/trametinib for BRAF V600+ melanoma and SLN metastasis >1mm (Category 1) OR
• High-dose Ipilimumab for SLN metastasis >1mm (Category 1) OR
• Interferon alfa


Adjuvant therapy for stage II and stage III melanoma
Source: Multiple, main source: ASCO

After surgery, the surgeon or medical oncologist may recommend adjuvant therapy for patients who are at higher risk for recurrence.
Adjuvant treatment options after melanoma surgery may include radiation therapy, immunotherapy, or joining a clinical trial that is researching new drug treatments.

Adjuvant radiation therapy
Sometimes, radiation therapy is considered after surgery to prevent recurrence. Research has shown that although this may reduce the risk of the melanoma coming back in the area that received radiation, it does not increase how long a person lives.

People who receive adjuvant radiation therapy experience side effects based on the area treated (see above). In general, a person’s overall quality of life is similar to that of people who do not receive it, according to the results of recent clinical trials. However, in those studies, some patients who received adjuvant radiation therapy had worse symptoms in the first year.

Adjuvant immunotherapy
The U.S. Food and Drug Administration (FDA) has approved 4 adjuvant immunotherapies for stage II and stage III melanoma:
high-dose interferon alfa-2b (Intron A), pegylated interferon alfa-2b (Sylatron), ipilimumab (Yervoy), and nivolumab (Opdivo).
Note: In April 2018, FDA approved adjuvant dabrafenib/trametinib for BRAF+ melanoma.

• High-dose interferon alfa-2b. (Intron A)
When given over a year, high-dose interferon alfa-2b has been shown to delay recurrences for some patients. However, it has not been shown to lengthen how long most people live.
There are substantial and common side effects to this treatment, including flu-like symptoms, such as fatigue, fever, chills, nausea, vomiting, and headache; rashes; hair thinning; and depression. Because of the side effects and lack of a lengthening of life for most patients who receive this treatment, the use of high-dose interferon is not recommended by all doctors who care for melanoma patients.

• Pegylated interferon alfa-2b.
This immunotherapy is given by weekly injection for up to 5 years and has been shown to delay recurrences for some patients. However, it has not been shown to lengthen how long people live.
The side effects are very similar to those of high-dose interferon alfa-2b. Because of the side effects and lack of a lengthening of life for most patients treated, the use of pegylated interferon is not recommended by all doctors who care for melanoma patients.

In 2011, pegylated interferon alpha-2b, which is characterized by a longer half-life and can be administered subcutaneously, was approved by the U.S. Food and Drug Administration for the adjuvant treatment of melanoma with microscopic or gross nodal involvement.
(Weekly subcutaneous pegylated interferon alpha-2b for up to 5 years.)

• Ipilimumab
Adjuvant ipilimumab for stage III melanoma was approved by the FDA in October 2015.
In patients with stage III melanoma, ipilimumab has been shown to delay recurrences and lengthen life for some patients.
The side effects of ipilimumab in patients with stage III melanoma are significant, however, and the rate of severe, life-threatening, or fatal side effects is around 50%.
Because this therapy may lengthen life yet has a high rate of severe side effects, it is important for oncologists and patients with stage III melanoma to discuss the risks and benefits of ipilimumab and decide together if the risks are worth the benefit.

Ipilimumab targets a molecule called cytotoxic T-lymphocyte associated molecule-4 (CTLA4). It works by taking the brakes off the immune system. Because this drug activates the immune system, it can trigger “autoimmune” side effects in which the patient’s own immune system attacks healthy cells in the body. These side effects can be serious and even life threatening. These side effects include significant colon inflammation (colitis), liver problems, skin reactions, nerve and hormone gland inflammation, and eye problems. Patients are also closely monitored for diarrhea, rashes, itching, and other side effects.

Note: FDA approved a prolonged high-dose adjuvant Ipilimumab regimen: 10 mg/kg every 3 weeks for 4 doses, then every 12 weeks for up to 3 years or until documented disease recurrence or unacceptable toxicities.
In contrast, FDA approved a shorter lower-dose Ipilimumab regimen: 3 mg/kg every 3 weeks for 4 doses, for the treatment of unresectable or metastatic melanoma.

Note: The optimal dose of ipilimumab in the adjuvant setting is unknown. Patients are fully accrued and data are pending from an intergroup trial, E1609 (NCT01274338), testing high-dose (10 mg) versus low-dose (3 mg) ipilimumab versus interferon. For patients with metastatic disease, the recommended dose is 3 mg/kg.

• Nivolumab.
The FDA has approved nivolumab as adjuvant treatment of stage III melanoma. Nivolumab is also approved to treat unresectable and/or metastatic melanoma.

In a multinational, randomized, double-blind trial (CheckMate 238), patients with stage IIIB, IIIC, or IV melanoma who underwent complete resection were randomly assigned (1:1) to receive nivolumab or ipilimumab.[Level of evidence: 1iDii] The primary endpoint was RFS.
Nivolumab was administered at the dose of 3 mg/kg intravenously (IV) every 2 weeks and ipilimumab was administered at the dose of 10 mg/kg every 3 weeks for four doses, then every 3 months for up to 1 year or until disease recurrence, along with corresponding placebo. (Source: NCI-PDQ)
Interim analysis was done, when all patients had a minimum follow-up of 18 months. The median RFS has not been reached in either treatment group. At 12 months, the rate of RFS for patients treated with nivolumab was 70.5% (95% confidence interval [CI], 66.1–74.0) versus 60.8% (95% CI, 56.0–65.2) in patients treated with ipilimumab. There were 154 (34%) recurrences or deaths in 453 patients treated with nivolumab versus 206 (45.5%) recurrences or deaths in 453 patients treated with ipilimumab (hazard ratio (HR) recurrence or death, 0.65; 97.56% CI, 0.51–0.83; P < .001). Subgroup analyses of RFS favored nivolumab regardless of PD-L1 expression or BRAF V600 mutation. (42% of patients in the study harbored BRAF mutations.). Patients treated with nivolumab had fewer adverse events (AEs),

• dabrafenib / trametinib
Note: In April 2018, FDA approved adjuvant dabrafenib/trametinib for BRAF+ melanoma.
(dabrafenib 150 mg p.o. bid + trametinib 2mg p.o. qd for 1 year.)

 

Adjuvant Therapy

Clinical Stage IA, 1B, 2A : Observation
Clinical Stage 2B, 2C : Observation or IFN-alfa (Category 2B)
Clinical/Pathologic Stage 3A, 3B, 3C :
    Observation OR
    Nivolumab (Category 1, Preferred) OR
    dabrafenib/trametinib for BRAF V600+ melanoma and SLN metastasis >1mm (Category 1) OR
    High-dose Ipilimumab for SLN metastasis >1mm (Category 1) OR
    IFN-alfa
Clinical/Pathologic Stage III (Clinically positive node(s)) :
    Same as above. OR
    Biochemotherapy (Category 2B)

Note:
Adjuvant Ipilimumab clinical trial excluded patients with SLN metastasis <1mm and patients who did not undergo CLND.
IFN can be given as high-dose IFN-alfa for 1 year or as peginterferon alfa-2b for up to 5 years. Adjuvant IFN improves DFS but not OS.



Adjuvant Therapy

• Treatment with nivolumab (240 mg) q2W for up to 1 year
• Combination ipilimumab + nivolumab: Nivolumab 1 mg/kg IV over 30 minutes followed by ipilimumab 3 mg/kg IV over 90 minutes repeated every 3 weeks for 4 doses, followed by Nivolumab 240 mg q2W for up to 1 year.
• Treatment with ipilimumab (10 mg/kg) 10 mg/kg every 3 weeks for 4 doses, then every 12 weeks for up to 3 years or until documented disease recurrence or unacceptable toxicities.
• Adjuvant high dose interferon alfa-2B for 1 year
• Pegylated interferon alfa-2b for 5 years
• Combination therapy with dabrafenib + trametinib for 1 year

 

 

Treatment Options for Unresectable Stage III and Stage IV Melanoma

Melanoma that has spread to the lymph nodes or developed other skin lesions nearby is called stage III melanoma. If melanoma has spread to other, distant parts of the body, such as distant lymph nodes or the liver, lung, brain, bone, or gastrointestinal tract, doctors call it stage IV melanoma. The most common distant places melanoma spreads to include the lung, liver, and brain.

Treatment recommendations for people with stage III melanoma that cannot be removed with surgery, called unresectable stage III, and stage IV melanoma are often the same and depend on a number of factors, including:
• The person’s age and overall health
• The locations and number of metastases
• How fast the disease is spreading
• The presence of specific genetic mutations in the tumor
• The patient’s preferences


Immunotherapy
• Anti-CTLA4 antibody
ipilimumab is approved by the FDA for the treatment of Unresectable Stage III and Stage IV Melanoma Treatment, and as adjuvant therapy for stage III melanoma.
Ipilimumab has been shown to shrink melanoma for 10% to 15% of patients. Some people with melanoma may benefit from ipilimumab treatment for years. Complete disappearance of melanoma has been seen in some patients, and it seems to be permanent in many such patients.

• Anti-PD-1 antibodies. nivolumab (Opdivo) and pembrolizumab (Keytruda).
Both nivolumab and pembrolizumab have been shown to shrink melanoma for 25% to 45% of patients, depending on when the treatment is given. They also cause fewer side effects than ipilimumab. Because of this, nivolumab and pembrolizumab are now being recommended as a first treatment option for people diagnosed with metastatic melanoma.

• Combining anti-PD-1 and anti-CTLA4 antibodies.
In September 2015, the FDA approved the immunotherapy combination of ipilimumab and nivolumab for patients with unresectable stage III or stage IV melanoma.
This combination is better than either drug alone in reducing the size and delaying growth of tumors. However, combining these drugs causes far more side effects and does not necessarily help people live longer.
The decision to give this combination therapy is often based on how fast the cancer is growing and where the cancer has spread.

• Interleukin-2 (IL-2, aldesleukin, Proleukin).
This drug activates T-cells, and it is sometimes given to patients with metastatic melanoma. The number of people for whom this treatment works is similar to that of ipilimumab (about 16%), with fewer than 10% of patients experiencing a complete response.
This treatment often has multiple and significant side effects. The most common side effects of IL-2 are low blood pressure, fever, chills, and a condition known as capillary leak syndrome. Capillary leak syndrome occurs when fluids and proteins leak from blood vessels, which can cause very low blood pressure and other dangerous effects. Patients treated with high-dose IL-2 require intensive monitoring by the health care team. IL-2 should be given by an experienced health care team familiar with the side effects of IL-2 treatment.

Targeted therapy
• BRAF inhibitors
The discovery that about 50% of melanomas have a mutated or activated BRAF gene has provided an important new direction in the treatment of melanoma.
There are 2 drugs that inhibit BRAF. Dabrafenib (Tafinlar) and vemurafenib (Zelboraf) have been FDA approved for people with both stage IV and unresectablestage III melanoma. These drugs, taken as a pill, are specifically used when the melanoma tumors have a V600E or V600K mutation in the BRAF gene.
In clinical trials, both drugs shrank the tumors in the majority of those patients. Vemurafenib was shown to extend patients’ survival by nearly a year, on average. Dabrafenib’s effect on overall survival was not formally tested.

Side effects of vemurafenib included skin problems, including rashes, hair thinning, thick or dry skin, sun sensitivity, and a less aggressive form of skin cancer called squamous cell carcinoma that can often be treated with minor surgery. Other side effects included joint pain, fatigue, nausea, fever, and hair thinning and curling. Dabrafenib seems to have fewer side effects like thick or dry skin and hair thinning, and it only rarely causes sun sensitivity.

• MEK inhibitors.
In May 2013, the FDA approved trametinib (Mekinist) for people with melanoma having a BRAF V600E or V600K mutation and who have been diagnosed with unresectable or metastatic melanoma.
This drug, which is taken as a tablet, specifically targets the MEK protein, which is involved in cancer growth and survival.
Trametinib was approved based on the results of a clinical study that showed patients with stage IIIC or IV melanoma who took this targeted therapy lived longer without the cancer getting worse than those who received chemotherapy.
The side effects of trametinib include an acne-like rash, nail inflammation, itching, dry skin, and diarrhea.

• Combining BRAF and MEK inhibitors.
In May 2014, the FDA approved the combination of dabrafenib with trametinib for melanoma that cannot be surgically removed or metastatic melanoma with a BRAF V600E or V600K mutation.
There have now been 2 clinical trials showing that the combination of dabrafenib and trametinib is associated with better tumor shrinkage rates, delay in tumor growth, and longer life compared to vemurafenib alone, in 1 study, and dabrafenib alone, in the other study.

The most common side effects of treatment with trametinib with dabrafenib include fever, chills, tiredness, rash, nausea, vomiting, diarrhea, abdominal pain, swelling in the hands and feet, cough, headache, joint pain, night sweats, decreased appetite, constipation, and muscle pain.
Interestingly, the combination of dabrafenib and trametinib reduces some side effects when compared to either of the medicines taken separately, including a lower rate of secondary skin cancers and rash.

In the fall of 2015, the FDA approved a second BRAF and MEK inhibitor combination, which consists of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib (Cotellic).
A clinical trial has shown that the combination of vemurafenib and cobimetinib is associated with better tumor shrinkage rates, delay in tumor growth, and longer life compared to vemurafenib alone.
The common side effects with this combination include tiredness, nausea, diarrhea, joint aches, sun sensitivity, rash, fever, liver irritation, and swelling in the hands and feet.

Because of the improved outcomes and reduced side effects of BRAF and MEK inhibitor combinations compared to BRAF or MEK inhibitors alone, it is standard practice to recommend 1 of these 2 approved combinations when targeted therapy is being offered to patients whose tumors have BRAF mutations.

• KIT inhibitors.
Researchers are also focusing on the development of treatments that target the KIT gene, which is mutated or present in increased numbers (extra copies of the gene) in some tumors in certain subtypes of melanoma, including lentigo maligna melanoma, mucosal melanoma, and acral lentiginous melanoma.
Drugs currently being tested in clinical trials for people with stage IV, mutated KIT melanoma include dasatinib (Sprycel), imatinib (Gleevec), and nilotinib (Tasigna).

Intralesional therapy
In late 2015, the FDA approved the use of talimogene laherparepvec (TVEC) for the treatment of unresectable stage III and stage IV melanoma. TVEC is a herpes virus designed in a laboratory to make an immune-stimulating hormone. This virus can infect and destroy melanoma cells. TVEC also helps stimulate the immune system to destroy other melanoma tumors. During intralesional therapy, TVEC is injected directly into 1 or more melanoma tumors.
Since TVEC has not been shown to cause significant shrinkage of non-injected tumors in most people, patients with metastatic disease are not usually offered this treatment. It may be offered, for example, to patients who have a tumor that can be felt during an exam and who have limited metastatic disease (a small number of or small tumors) elsewhere, such as the lungs or liver. TVEC is being studied in combination with other medications to improve its effectiveness.

Chemotherapy
Traditional types of chemotherapy are still used to treat melanoma, but they are usually no longer used as first-line therapy.
Common drugs used for melanoma include dacarbazine (DTIC-Dome), which is the only FDA-approved chemotherapy for melanoma.
Temozolomide (Methazolastone, Temodar) is essentially an oral version of DTIC, and it is used for the treatment of stage IV melanoma.

Both DTIC and temozolomide have been shown to shrink melanoma for about 12% to 15% of patients. However, no clinical trials have tested whether these drugs increase how long people with melanoma live after treatment. Both DTIC and temozolomide have a limited number of side effects.

Other chemotherapies used to treat melanoma include cisplatin (Platinol), fotemustine (Muphoran), lomustine (CeeNU), the taxanes (a group of drugs that includes docetaxel [Taxotere] and paclitaxel [Taxol]), and vinblastine (Velban, Velsar).
Combinations of chemotherapy drugs, such as paclitaxel plus carboplatin or cisplatin combined with vinblastine and DTIC may be used. Some chemotherapy drug combinations may have a higher chance of causing melanoma to shrink, but they also cause more side effects.

Isolated limb infusion therapy
Sometimes melanoma may spread and appear as a number of tumors that develop in the leg or arm. In these situations, there are too many tumors for surgery to be possible or helpful. A doctor may recommend isolated limb infusion or perfusion with chemotherapy.

During this treatment, a tourniquet is placed on the arm or leg before high doses of chemotherapy are given. The tourniquet keeps the chemotherapy in the arm or leg and prevents it from being transported throughout the body. Around 50% to 80% of tumors located in the area where the chemotherapy is circulated respond to this type of treatment. While tumor shrinkage is usually temporary, melanoma may be controlled for a year or more in some patients. Researchers are also testing the effectiveness of combining isolated limb infusion therapy with other medicine.

Radiation therapy
Radiation therapy may be used to treat melanoma that has spread in several ways.

Sometimes melanoma that has spread causes symptoms, such as bone pain or headaches, that radiation therapy can help relieve. This is called palliative radiation therapy.
For some patients, palliative radiation therapy is given to an entire organ with several small doses of radiation, such as to the entire brain using whole-brain radiation therapy.
Other times, 1 or just a few high doses of radiation therapy are given using a linear accelerator ("linac"), Gamma Knife, CyberKnife, or TomoTherapy units. This is called stereotactic radiosurgery, stereotactic ablative radiation therapy, or stereotactic body radiation therapy. It usually works best for just 1 or a few tumors in the brain or elsewhere in the body.

Radiation therapy may be used when cancer has extensive spread to the lymph nodes or skin and cannot be removed by surgery. Researchers also are testing the effectiveness of combining radiation therapy and medicines for melanoma.

Surgery
If the melanoma has spread to a single or a few distant parts of the body or has come back after treatment, the surgical removal of cancer may help control the disease. However, if there are too many tumors, surgery may not be helpful.

Treating brain metastases
The brain is one of the most common places to which melanoma spreads. Unfortunately, the presence of brain metastases is linked with a very poor prognosis. Less than 50% of people with melanoma that has spread to the brain live 6 months.
Because of this poor prognosis and because of the perceived difficulty in getting chemotherapy drugs into brain tissue (called the blood-brain barrier), people with melanoma that has spread to the brain have typically not been allowed into clinical trials. Fortunately, this is beginning to change, and there are clinical trials for patients with melanoma and brain metastases.

Currently, the following treatments may be recommended for melanoma that has spread to the brain:
• Radiation therapy. High-dose radiation therapy given using stereotactic techniques is often used when there are only a few metastatic tumors in the brain. These techniques are highly effective for getting rid of existing tumors. However, they do not prevent new tumors from developing.
The entire brain can be treated with radiation therapy, called whole-brain radiation therapy. However, because the dose of radiation used to treat the entire brain is lower, this type of treatment usually does not shrink tumors.

• BRAF inhibitors. For people with melanoma that has a BRAF mutation, drugs such as dabrafenib and vemurafenib may be recommended. These drugs easily penetrate into the brain. Clinical trials have shown that melanoma tumors in the brain shrink around 40% to 50% of the time.

• Immunotherapy. Ipilimumab, nivolumab, and pembrolizumab are currently being used in clinical trials to treat people with melanoma that has spread to the brain.

 

Systemic therapy for unresectable Stage III and Stage IV Melanoma

First-line therapy
• pembrolizumab (Category 1)
      2 mg/kg q3w for up to 2 years.
• nivolumab (Category 1)
      3 mg/kg q2w for up to 2 years.
• nivolumab + Ipilimumab (Category 1)
      Ipilimumab 3 mg/kg IV over 90 minutes plus nivolumab 1 mg/kg IV over 60 minutes repeated every 3 weeks for 4 doses followed by nivolumab 240 mg IV over 60 minutes repeated every 2 weeks (for up to 2 years) or until disease progression or unacceptable toxicity.
First-line therapy
If BRAF V600+ (Preferred if clinically needed for early response):
• dabrafenib / trametinib (Category 1)
• vemurafenib / cobimetinib (Category 1)
• encorafenib / benimetinib (Category 1)

Second-line or Subsequent therapy
• pembrolizumab
• nivolumab
• nivolumab + Ipilimumab
• dabrafenib / trametinib
• vemurafenib / cobimetinib
• encorafenib / benimetinib
• Ipilimumab
    3 mg/kg IV over 90 minutes repeated every 3 weeks for a total of 4 doses. Doses may be delayed for toxicity; however, all treatment must be administered within 16 weeks • High-dose IL-2
• Cytotoxic agents
• Imatinib for tumors with KIT mutation
• Best supportive care

Factors to consider when selecting second-line therapy

• Disease characteristics
    – BRAF mutated disease versus wild type
    – NRAS, KIT mutations
• Prior therapies
    – Switch classes as a general rule
    – Best response to therapy
    – Setting (adjuvant versus metastatic)
    – Timing of relapse in relation to therapy
• Prior toxicities


For patients who progressed on single-agent checkpoint immunotherapy, nivolumab/ipilimumab combination therapy is a reasonable treatment option.
For patients who experience disease control (CR, PR, or SD) and have no residual toxicity, but subsequently experience disease progression/relapse >3 months after treatment discontinuation, re-induction with the same agent or same class of agents may be considered.

 

 

 

Intraocular (Uveal) Melanoma

Melanoma of the uveal tract (iris, ciliary body, and choroid), though rare, is the most common primary intraocular malignancy in adults. The mean age-adjusted incidence of uveal melanoma in the United States is approximately 4.3 new cases per million people.
Uveal melanoma is diagnosed mostly at older ages, with a progressively rising, age-specific, incidence rate that peaks near the age of 70 years.
Host susceptibility factors associated with the development of this cancer include:
•Caucasian race. •Light eye color. •Fair skin. •The ability to tan.
In view of these susceptibility factors, numerous observational studies have attempted to explore the relationship between sunlight exposure and risk of uveal melanoma. To date, these studies have found only weak associations or yielded contradictory results. Similarly, there is no consistent evidence that occupational exposure to UV light or other agents is a risk factor for uveal melanoma.

Uveal melanomas differ significantly from cutaneous melanomas. ln one series, 83% of 186 uveal melanomas were found to have a constitutively active somatic mutation in GNAQ or GNA11.


Anatomic Location

Uveal melanomas can arise in the anterior (iris) or the posterior (ciliary body or choroid) uveal tract. Iris melanomas have the best prognosis, whereas melanomas of the ciliary body have the least favorable prognosis. Most uveal tract melanomas originate in the choroid. The ciliary body is less commonly a site of origin, and the iris is the least common. The comparatively low incidence of iris melanomas has been attributed to the characteristic features of these tumors, i.e., they tend to be small, slow growing, and relatively dormant in comparison with their posterior counterparts. Iris melanomas rarely metastasize. Melanomas of the posterior uveal tract generally have a more malignant, histologic appearance; are detected later; and metastasize more frequently than iris melanomas. The typical choroidal melanoma is a brown, elevated, dome-shaped subretinal mass. The degree of pigmentation ranges from dark brown to totally amelanotic.

Most uveal melanomas are initially completely asymptomatic. As the tumor enlarges, it may cause distortion of the pupil (iris melanoma), blurred vision (ciliary body melanoma), or markedly decreased visual acuity caused by secondary retinal detachment (choroidal melanoma). Serous detachment of the retina may occur. If extensive detachment occurs, secondary angle-closure glaucoma occasionally develops. Clinically, several lesions simulate uveal melanoma, including metastatic carcinoma, posterior scleritis, and benign tumors, such as nevi and hemangiomas.


Anatomy of Eye

Iris
The iris is the colored area at the front of the eye (the "eye color"). It can be seen through the clear cornea. The pupil is in the center of the iris and it changes size to let more or less light into the eye. Intraocular melanoma of the iris is usually a small tumor that grows slowly and rarely spreads to other parts of the body.
Ciliary body
The ciliary body is a ring of tissue with muscle fibers that change the size of the pupil and the shape of the lens. It is found behind the iris. Changes in the shape of the lens help the eye focus. The ciliary body also makes the clear fluid that fills the space between the cornea and the iris. Intraocular melanoma of the ciliary body is often larger and more likely to spread to other parts of the body than intraocular melanoma of the iris.
Choroid
The choroid is a layer of blood vessels that bring oxygen and nutrients to the eye. Most intraocular melanomas begin in the choroid. Intraocular melanoma of the choroid is often larger and more likely to spread to other parts of the body than intraocular melanoma of the iris.

Diagnosis

Careful examination by an experienced clinician remains the most important test to establish the presence of intraocular melanoma. It is not possible to distinguish a small uveal melanoma from a nevus. Small uveal lesions are often observed for growth to make a diagnosis of melanoma. Clinical findings that may help to identify melanoma include:
•Tumor thickness of more than 2 mm.
•Subretinal fluid.
•Visual symptoms.
•Orange pigment on the tumor surface.
•A tumor margin touching the optic disc.

Ancillary diagnostic testing, including fluorescein angiography and ultrasonography, can be extremely valuable in establishing and/or confirming the diagnosis. In a large, retrospective, single-center series of 2,514 consecutive patients with choroidal nevi, the progression rates to melanoma at 5, 10, and 15 years were 8.6%, 12.8%, and 17.3%, respectively.


Prognostic Factors

A number of factors influence prognosis. The most important factors include the following:
•Cell type. (See Cellular Classification of Intraocular [Uveal] Melanoma section).
•Tumor size.
•Location of the anterior margin of the tumor.
•Degree of ciliary body involvement.
•Extraocular extension.

Several additional microscopic features can affect the prognosis of intraocular melanoma, including:
•Mitotic activity.
•Lymphocytic infiltration.
•Fibrovascular loops (possibly).

Cell type is the most commonly used predictor of outcome following enucleation, with spindle-A cell melanomas carrying the best prognosis and epithelioid cell melanomas carrying the least favorable prognosis. Nevertheless, most tumors have an admixture of cell types, and there is no clear consensus regarding the proportion of epithelioid cells that constitutes designation of a tumor as mixed or epithelioid.

Extraocular extension, recurrence, and metastasis are associated with an extremely poor prognosis, and long-term survival cannot be expected. The 5-year mortality rate associated with metastasis from ciliary body or choroidal melanoma is approximately 30%, compared with a rate of 2% to 3% for iris melanomas.


Cellular Classification of Intraocular (Uveal) Melanoma

Primary intraocular melanomas originate from melanocytes in the uveal tract. Four distinct cellular types are recognized in intraocular melanoma (revised Callender classification):
1.Spindle-A cells (spindle-shaped cells with slender nuclei and lacking visible nucleoli).
2. Spindle-B cells (spindle-shaped cells with larger nuclei and distinct nucleoli).
3. Epithelioid cells (larger polygonal cells with one or more prominent nucleoli).
4. Intermediate cells (similar to but smaller than epithelioid cells).

Most primary intraocular melanomas contain variable proportions of epithelioid, spindle-A, and spindle-B cells (mixed-cell melanomas). Pure epithelioid-cell primary melanomas are infrequent (approximately 3% of cases). In the Collaborative Ocular Melanoma Study, mixed-cell type melanomas predominated (86% of cases).



Staging and Treatment

(See National Cancer Institute (NCI) - Melanoma Treatment PDQ   At PubMed)

T1 Tumor limited to the iris.
T2 Tumor confluent with or extending into the ciliary body, choroid, or both.
T3 Tumor confluent with or extending into the ciliary body, choroid, or both, with scleral extension.
T4 Tumor with extrascleral extension.


Iris melanomas have relatively good outcomes with a 5-year survival rate of more than 95%. They are predominantly of the spindle-cell type and are usually smaller in size than posterior melanomas because of earlier detection. Conservative management is generally advocated whenever possible, but surgical intervention may be justified with unequivocal tumor growth or with extensive disease at initial examination.

The management of small choroidal melanomas is controversial, and it is not clear whether treatment of small tumors prevents metastasis. The natural history of small choroidal melanoma is poorly understood. Small, pigmented, choroidal lesions cannot always be differentiated reliably on examination. Growth is a presumed indicator of malignant potential. The likelihood of progression from the time of diagnosis to the time when tumor growth warrants treatment has not been well characterized. Some ophthalmologists advocate observation. This has been justified on several grounds, including the difficulty with establishing a correct diagnosis, the lack of any documented efficacy for globe-conserving treatments, and concerns for severe treatment-related morbidity. Others have advocated earlier therapeutic intervention.

Although patients diagnosed with small choroidal tumors were not eligible for participation in the Collaborative Ocular Melanoma Study (COMS), these patients were offered participation in a prospective follow-up study to evaluate the natural history of small lesions. Two-year and 5-year tumor growth estimates of 21% and 31%, respectively, were reported.[5] Clinical risk factors associated with tumor growth included:

•Increased tumor thickness.
•Presence of subretinal fluid.
•Orange pigmentation.
•Absence of drusen.
•Absence of retinal pigment.
•Margin at the optic disc.
•Epithelial changes surrounding the tumor

No effective method of systemic treatment has been identified for patients with metastatic ocular melanoma. Available clinical trials should be considered as an option for these patients.